[Federal Register Volume 80, Number 130 (Wednesday, July 8, 2015)]
[Rules and Regulations]
[Pages 38915-38940]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-16659]



[[Page 38915]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 310, 314, and 600

[Docket No. FDA-2011-N-0898]
RIN 0910-AG88


Permanent Discontinuance or Interruption in Manufacturing of 
Certain Drug or Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
amending its regulations to implement certain drug shortages provisions 
of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended 
by the Food and Drug Administration Safety and Innovation Act (FDASIA). 
The rule requires all applicants of covered approved drugs or 
biological products--including certain applicants of blood or blood 
components for transfusion and all manufacturers of covered drugs 
marketed without an approved application--to notify FDA electronically 
of a permanent discontinuance or an interruption in manufacturing of 
the product that is likely to lead to a meaningful disruption in supply 
(or a significant disruption in supply for blood or blood components) 
of the product in the United States.

DATES: The rule is effective September 8, 2015.

FOR FURTHER INFORMATION CONTACT: Jouhayna Saliba, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 6206, Silver Spring, MD 20993, 301-796-
1300; or Stephen Ripley, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, rm. 
7301, Silver Spring, MD 20993, 240-402-7911.

SUPPLEMENTARY INFORMATION: 

Table of Contents

Executive Summary
Purpose of the Rule
Summary of the Major Provisions of the Rule
Summary of the Costs and Benefits of the Rule
 I. Introduction
II. The Proposed Rule
III. Description of the Final Rule
    A. Persons Subject to the Rule
    B. Products Covered by the Rule
    C. Notification of a Permanent Discontinuance or an Interruption 
in Manufacturing
IV. Comments on the Proposed Rule
    A. Persons Subject to the Rule
    B. Products Covered by the Rule
    C. Notification of a Permanent Discontinuance or an Interruption 
in Manufacturing
    D. Other Issues Raised
V. Legal Authority
VI. Economic Analysis of Impacts
    A. Introduction
    B. Summary
VII. Paperwork Reduction Act of 1995
VIII. Federalism
IX. Environmental Impact
X. References

Executive Summary

Purpose of the Rule

    FDASIA (Pub. L. 112-144) significantly amended provisions in the 
FD&C Act related to drug shortages. Among other things, FDASIA amended 
section 506C of the FD&C Act (21 U.S.C. 356c) to require all 
manufacturers of certain drugs to notify FDA of a permanent 
discontinuance or an interruption in manufacturing of these drugs 6 
months in advance of the permanent discontinuance or interruption in 
manufacturing, or as soon as practicable. FDASIA also added section 
506E to the FD&C Act (21 U.S.C. 356e), requiring FDA to maintain a 
current list of drugs that are determined by FDA to be in shortage in 
the United States and to include on that public list certain 
information about those shortages. Finally, FDASIA permits FDA to apply 
section 506C to biological products by regulation and requires FDA to 
issue a final rule implementing certain drug shortages provisions in 
FDASIA by January 9, 2014. FDA believes this final rule will improve 
FDA's ability to identify potential drug shortages and to prevent or 
mitigate the impact of these shortages.

Summary of the Major Provisions of the Rule

    The rule modifies FDA's regulations to implement sections 506C and 
506E of the FD&C Act as amended by FDASIA. Sections 310.306, 
314.81(b)(3)(iii), and 600.82 (21 CFR 310.306, 314.81(b)(3)(iii), and 
600.82) require all applicants of certain approved drugs or biological 
products,\1\ including applicants of blood or blood components \2\ for 
transfusion (``blood or blood components'') that manufacture a 
significant percentage of the U.S. blood supply, and all manufacturers 
of certain drugs marketed without an approved application (``unapproved 
drug manufacturers''), to notify FDA electronically of a permanent 
discontinuance or an interruption in manufacturing of the product that 
is likely to lead to a meaningful disruption in supply (for drugs and 
biological products other than blood or blood components) or a 
significant disruption in supply (for blood or blood components) of the 
product in the United States. Applicants \3\ are required to notify FDA 
of a permanent discontinuance or an interruption in supply if the drug 
or biological product is a prescription product that is life 
supporting, life sustaining, or intended for use in the prevention or 
treatment of a debilitating disease or condition, including any such 
drug used in emergency medical care or during surgery, and excluding 
radiopharmaceutical products (referred to in this document as 
``covered'' drugs or biological products). The rule requires 
notification to FDA at least 6 months prior to date of the permanent 
discontinuance or interruption in manufacturing, or, if 6 months' 
advance notice is not possible, as soon as practicable thereafter, but 
in no case later than 5 business days after the permanent 
discontinuance or interruption in manufacturing occurs.
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    \1\ As used throughout this document, the term ``biological 
product'' refers to a biological product licensed under section 351 
of the Public Health Service Act (42 U.S.C. 262), other than a 
biological product that also meets the definition of a device in 
section 201(h) of the FD&C Act (21 U.S.C. 321(h)). This rule does 
not apply to biological products that also meet the definition of a 
device in section 201(h) of the FD&C Act.
    \2\ As used throughout this rule, the term ``blood and blood 
components'' refers to blood and blood components for transfusion 
other than Source Plasma, which is outside the scope of this rule.
    \3\ In this document, for the sake of convenience, we 
collectively refer to applicants holding an abbreviated new drug 
application (ANDA), new drug application (NDA), or biologics license 
application (BLA) and unapproved drug manufacturers subject to this 
rule as the ``applicant'' (although we recognize that an unapproved 
drug manufacturer is not an applicant). We may also individually 
refer to the ANDA, NDA, and BLA applicant or unapproved drug 
manufacturer as needed, if the context requires distinguishing 
between these entities.
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    The rule also provides that FDA will issue a noncompliance letter 
to an applicant for failure to notify FDA under the rule; specifies 
minimum information that must be included in the notification; codifies 
FDA's current practice of publicly disseminating information on 
shortages and maintaining public lists of drugs and biological products 
in shortage (subject to certain confidentiality protections); and 
defines the terms ``drug shortage,'' ``biological product shortage,'' 
``meaningful disruption,'' ``significant disruption,'' ``life 
supporting or life sustaining,'' and ``intended for use in the 
prevention or treatment of a debilitating disease or condition.''

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    Finally, the rule includes a technical revision to Sec.  20.100 (21 
CFR 20.100) (public disclosure regulations) to include a cross-
reference to the disclosure provisions in Sec. Sec.  310.306, 314.81, 
and 600.82; and removes Sec.  314.91 related to reducing the 6-month 
notification period for ``good cause,'' since it is no longer 
applicable under section 506C of the FD&C Act as amended by FDASIA.

Summary of the Costs and Benefits of the Rule

    The rule imposes annual reporting costs of up to $16,827 on those 
applicants affected by the rule, and up to $441,000 on FDA in review 
costs. Undertaking mitigation strategies, as measured by labor 
resources, is estimated to cost FDA between $1.85 and $5.94 million, 
and industry between $2.97 and $9.55 million. We also estimate annual 
costs for industry between $9.57 and $30.97 million associated with 
increasing production. Estimated total annual costs of the interactions 
between industry and FDA range between $14.54 and $46.92 million. 
Discounting over 20 years, annualized quantified benefits from avoiding 
the purchase of alternative products, managing product shortages, and 
life-years gained, would range from $30.45 million to $98.65 million 
using a 3 percent discount rate, and from $30.39 million to $98.42 
million using a 7 percent discount rate. The public health benefits, 
mostly nonquantified, include the value of information that would 
assist FDA, manufacturers, health care providers, and patients in 
evaluating, mitigating, and preventing shortages of drugs and 
biological products that could otherwise result in delayed patient 
treatment or interruption in clinical trial development.

I. Introduction

    Recent experience with shortages of drugs and biological products 
in the United States has shown the serious and immediate effects they 
can have on patients and health care providers. According to 
information from FDA's drug and biological product shortages databases, 
the number of drug and biological product shortages quadrupled from 
approximately 61 in 2005 to more than 250 shortages in 2011. Although 
the number of new drug shortages significantly decreased in 2012 to 117 
shortages, in 2013 to 44 shortages, and stayed at 44 new shortages in 
2014, drug and biological product shortages still represent an ongoing 
challenge to public health.\4\ Shortages can involve critical drugs 
used to treat cancer, to provide required parenteral nutrition, or to 
address other serious medical conditions and can delay or deny needed 
care for patients. Shortages can also result in providers prescribing 
second-line alternatives, which may be less effective or higher risk 
than first-line therapies.
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    \4\ Information on product shortages can be found at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (for products 
regulated by the Center for Drug Evaluation and Research) and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (for products regulated by the Center for Biologics 
Evaluation and Research).
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    In response to the increasing concerns about the impact of 
shortages on health care in the United States, on October 31, 2011, 
President Obama issued Executive Order 13588 directing FDA to ``take 
steps that will help to prevent and reduce current and future 
disruptions in the supply of lifesaving medicines'' and noting that 
``one important step is ensuring that FDA and the public receive 
adequate advance notice of shortages whenever possible'' (Ref. 1). In 
response to the Executive Order's directive to address the growing 
problem of drug shortages, FDA published an interim final rule (IFR) on 
December 19, 2011 (effective January 18, 2012), modifying the 
regulation at Sec.  314.81 related to drug shortages (76 FR 78530).
    As a result of the Executive order and IFR, early notifications to 
FDA of potential shortages increased from an average of 10 a month 
before the Executive order to approximately 60 a month in the months 
after the IFR. This dramatic increase in early notifications enabled 
FDA to work with manufacturers and other stakeholders to successfully 
prevent numerous shortages by using tools such as:
     Working with manufacturers to resolve manufacturing and 
quality issues contributing to short supply.
     Expediting FDA inspections and reviews of submissions from 
manufacturers to prevent and/or alleviate shortages.
     Identifying and working with manufacturers willing to 
initiate or increase production to cover expected gaps in supply.
     Exercising regulatory flexibility and discretion in 
appropriate circumstances, if this would not cause undue risk to 
patients.

FDA was able to prevent just under 200 drug and biological product 
shortages in 2011, more than 280 such shortages in 2012, 170 shortages 
in 2013, and 101 shortages in 2014.
    In July 2012, FDASIA amended the FD&C Act to modify existing drug 
shortages requirements and to add new drug shortages provisions. 
Section 506C(i) of the FD&C Act, added by FDASIA, directs FDA to adopt 
a final rule to implement the drug shortages provisions. The final rule 
supersedes the IFR.

II. The Proposed Rule

    In the Federal Register of November 4, 2013 (78 FR 65904), FDA 
published a proposed rule to implement certain drug shortages 
provisions of the FD&C Act, as amended by FDASIA.\5\ The preamble to 
the proposed rule explained that section 1001 of FDASIA made 
substantial changes to section 506C of the FD&C Act related to 
reporting and addressing ``permanent discontinuances'' or 
``interruptions in manufacturing'' of certain drug products. Most 
significantly, section 506C of the FD&C Act as amended:
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    \5\ Section 506C(i)(4) of the FD&C Act specifies that in 
promulgating a regulation to implement the FD&C Act's drug shortage 
provisions, FDA must issue a notice of proposed rulemaking that 
includes the proposed rulemaking and provide a period of no less 
than 60 days for public comment on the proposed rule.
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     Requires all manufacturers of a prescription drug that is 
life supporting, life sustaining, or intended for use in the prevention 
or treatment of a debilitating disease or condition, including any such 
drug used in emergency medical care or during surgery, and excluding 
radiopharmaceutical products, to notify FDA of a permanent 
discontinuance in the manufacture of the drug or an interruption in the 
manufacturing of the drug that is likely to lead to a meaningful 
disruption in the supply of that drug in the United States at least 6 
months prior to the date of the permanent discontinuance or 
interruption in manufacturing, or, if that is not possible, as soon as 
practicable.
     Requires the manufacturer to include in the notification 
the reason for the permanent discontinuance or interruption in 
manufacturing.
     Requires FDA to issue a letter to a ``person'' who fails 
to comply with the notification requirements in section 506C.
     Defines the terms ``drug,'' ``drug shortage,'' and 
``meaningful disruption,'' and requires FDA to define the terms ``life 
supporting,'' ``life sustaining,'' and ``intended for use in the 
prevention or treatment of a debilitating disease or condition.''
     Permits FDA to apply section 506C to biological products, 
including vaccines and plasma-derived products

[[Page 38917]]

and their recombinant analogs, if FDA determines the inclusion would 
benefit public health, taking into account existing supply reporting 
programs and aiming to reduce duplicative notifications.
     Requires FDA to distribute information on drug shortages 
to the public, to the maximum extent possible, subject to certain 
confidentiality protections.
    In addition to modifying section 506C, FDASIA added several new 
drug shortage-related sections to the FD&C Act, including section 506E. 
Section 506E of the FD&C Act requires FDA to maintain an up-to-date 
list of drugs that are determined by FDA to be in shortage, including 
the names and the National Drug Codes (NDCs) of such drugs in shortage, 
the name of each manufacturer of the drug, the reason for each shortage 
as determined by FDA (choosing from a list of reasons enumerated in the 
statute), and the estimated duration of each shortage. Section 506E of 
the FD&C Act also includes confidentiality provisions.
    The Agency proposed to implement sections 506C and 506E of the FD&C 
Act by amending Sec.  314.81(b)(3)(iii) (permanent discontinuance or 
interruption in manufacturing of approved prescription drugs) and Sec.  
20.100 (cross-reference to disclosure provisions); adding new Sec.  
310.306 (permanent discontinuance or interruption in manufacturing of 
marketed prescription unapproved new drugs) and Sec.  600.82 (permanent 
discontinuance or interruption in manufacturing of prescription 
biological products); and removing Sec.  314.91 (reduction in the 
discontinuance notification period) (see 78 FR 65904).
    FDA provided 60 days for public comment on the proposed rule. Based 
on the comments received and FDA's experience to date receiving 
notifications, maintaining public lists of drug and biological product 
shortages, and working with manufacturers and stakeholders to prevent 
and mitigate drug and biological product shortages, the Agency is 
finalizing the rule as proposed.

III. Description of the Final Rule

A. Persons Subject to the Rule

    Sections 310.306, 314.81(b)(3)(iii), and 600.82 require 
notification to FDA of a permanent discontinuance or an interruption in 
manufacturing of a covered drug or biological product. The following 
persons are subject to these notification requirements:
     All applicants with an approved NDA or ANDA for a covered 
drug product (Sec.  314.81(b)(3)(iii)).
     All applicants with an approved BLA for a covered 
biological product, other than blood or blood components (Sec.  
600.82(a)(1)).
     Applicants with an approved BLA for blood or blood 
components, if the applicant is a manufacturer of a significant 
percentage of the U.S. blood supply (Sec.  600.82(a)(2)).
     All manufacturers of a covered drug product marketed 
without an approved NDA or ANDA (Sec.  310.306, which applies Sec.  
314.81(b)(3)(iii) in its entirety to covered drug products marketed 
without an approved NDA or ANDA).
    Section 506C of the FD&C Act as amended by FDASIA requires a 
``manufacturer'' to notify FDA of a permanent discontinuance or an 
interruption in manufacturing. The rule requires the ANDA, NDA, or BLA 
applicant (for approved drugs or biological products) or the unapproved 
drug manufacturer (for marketed, unapproved drugs) to notify FDA of a 
permanent discontinuance or an interruption in manufacturing.
    For purposes of section 506C of the FD&C Act, under the rule an 
ANDA, NDA, or BLA applicant is considered the manufacturer of an 
approved, covered product, even if the ANDA, NDA, or BLA applicant 
contracts that function out to another entity. In other words, the rule 
makes clear that for approved, covered drugs and biological products, 
the ANDA, NDA, or BLA applicant bears the responsibility for reporting 
to FDA a permanent discontinuance or an interruption in manufacturing, 
whether the product is manufactured by the applicant itself or for the 
applicant under contract with one or more different entities. As such, 
the ANDA, NDA, or BLA applicant should establish a process with any 
relevant contract manufacturer, active pharmaceutical ingredient (API) 
supplier, or other non-applicant entity that ensures the applicant's 
compliance with this rule.
    Section 506C(i)(3) of the FD&C Act, as amended by FDASIA, directs 
FDA to ``take into account any supply reporting programs [for 
biological products] and . . . aim to reduce duplicative notification'' 
in applying section 506C to biological products by regulation. 
Accordingly, with respect to blood or blood components, the rule 
applies only to applicants that are manufacturers of a ``significant 
percentage of the United States blood supply.'' As described more fully 
in sections III.B.2.c and III.C.1.b.ii, FDA believes that this approach 
with respect to blood or blood components will ensure that the Agency 
receives information that is essential to preventing shortages of these 
products, without unnecessarily duplicating existing systems and 
without being unduly burdensome for industry. FDA intends to consider 
an applicant that holds a BLA for blood or blood components to be a 
manufacturer of a ``significant percentage'' of the U.S. blood supply 
if the applicant manufactures 10 percent or more of the U.S. blood 
supply.\6\
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    \6\ Based on 2011 National Blood Collection and Utilization 
Survey (NBCUS) data, 10 percent or more of the U.S. blood supply 
would mean more than 1.5 million units of whole blood annually or 
approximately 125,000 units per month. We note, however, that these 
numbers may fluctuate year to year. See 2011 National Blood 
Collection and Utilization Survey Report, available at http://www.hhs.gov/ash/bloodsafety/nbcus/.
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B. Products Covered by the Rule

1. Prescription Drug and Biological Products That Are Life Supporting, 
Life Sustaining, or Intended for Use in the Prevention or Treatment of 
a Debilitating Disease or Condition
    The rule applies to all prescription drug products approved under 
an NDA or ANDA (Sec.  314.81(b)(3)(iii)), all marketed unapproved 
prescription drug products (Sec.  310.306), and all prescription 
biological products approved under a BLA (Sec.  600.82) that are:
     Life supporting; life sustaining; or intended for use in 
the prevention or treatment of a debilitating disease or condition, 
including any such product used in emergency medical care or during 
surgery; and
     Not radiopharmaceutical products.\7\
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    \7\ With respect to blood and blood components for transfusion, 
the reporting requirement applies only to an applicant that 
manufactures a significant percentage of the U.S. blood supply.
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    FDASIA does not define the terms ``life supporting,'' ``life 
sustaining,'' or ``intended for use in the prevention or treatment of a 
debilitating disease or condition,'' but instead requires FDA to define 
them (section 506C(i)(2) of the FD&C Act). Sections 
314.81(b)(3)(iii)(f) and 600.82(f) define a ``life supporting or life 
sustaining'' drug or biological product as one that is ``essential to, 
or that yields information that is essential to, the restoration or 
continuation of a bodily function important to the continuation of 
human life.'' As explained in the preamble to the proposed rule (78 FR 
65904 at 65909), this definition of ``life supporting or life 
sustaining'' is consistent with language used to describe this term in 
the preamble to the final rule implementing pre-FDASIA section 506C (72 
FR 58993 at 58994, October 18, 2007), and in

[[Page 38918]]

medical device regulations (see 21 CFR 821.3(g)).
    The final rule defines ``intended for use in the prevention or 
treatment of a debilitating disease or condition'' to mean ``intended 
for use in the prevention or treatment of a disease or condition 
associated with mortality or morbidity that has a substantial impact on 
day-to-day functioning'' (Sec. Sec.  314.81(b)(3)(iii)(f) and 
600.82(f)). FDA equates ``debilitating disease or condition'' with 
``serious disease or condition'' under this definition, and we have 
defined it according to the definition of ``serious'' found in Sec.  
312.300 (21 CFR 312.300), which governs expanded access to 
investigational new drugs. This definition of ``intended for use in the 
prevention or treatment of a debilitating disease or condition'' is 
also consistent with our discussion of the term in the preamble to the 
proposed rule implementing the pre-FDASIA section 506C (65 FR 66665 at 
66666, November 7, 2000).
    It is important to note that the definitions of ``life supporting 
or life sustaining'' and ``intended for use in the prevention or 
treatment of a debilitating disease or condition'' are, in important 
respects, different than FDA's definition of ``medically necessary'' as 
used in the context of the existing Center for Drug Evaluation and 
Research (CDER) Manual of Policies and Procedures (MAPP) on shortages 
of CDER-regulated products (CDER MAPP 4190.1 Rev. 2) (Ref. 2) and the 
existing Center for Biologics Evaluation and Research (CBER) Standard 
Operating Policy and Procedure (SOPP) on shortages of CBER-regulated 
products (CBER SOPP 8506) (Ref. 3). In general, FDA considers a product 
to be medically necessary under the internal MAPP and SOPP if there is 
no other product that is judged by CDER or CBER medical staff to be an 
appropriate substitute or there is an inadequate supply of an 
acceptable alternative, as determined by appropriate CDER and CBER 
personnel. In contrast, under this rule, an applicant is required to 
notify FDA of a permanent discontinuance or an interruption in 
manufacturing of a drug or biological product that is life supporting, 
life sustaining, or intended for use in the prevention or treatment of 
debilitating disease or condition, whether or not the product is 
considered ``medically necessary'' under the MAPP or SOPP. Under the 
MAPP and SOPP, FDA uses the definition of medically necessary to 
prioritize the Agency's response to specific shortages or potential 
shortages and to allocate resources appropriately.
2. Biological Products
    Section 506C of the FD&C Act, as amended, states that for purposes 
of section 506C, the term ``drug'' does not include biological products 
as defined in section 351(i) of the Public Health Service Act, unless 
the Secretary of Health and Human Services (HHS) (the Secretary) 
applies section 506C to such products by regulation. Section 506C(i)(3) 
of the FD&C Act provides that FDA may, by regulation, apply section 
506C to biological products, ``including plasma products derived from 
human plasma protein and their recombinant analogs'' if ``the Secretary 
determines that such inclusion would benefit the public health,'' 
taking into account ``any [existing] supply reporting programs'' and 
aiming to reduce ``duplicative notification.'' Additionally, FDA may 
apply section 506C of the FD&C Act to vaccines, but the Secretary must 
determine whether notification of a vaccine shortage to the Centers for 
Disease Control and Prevention (CDC) under its ``vaccine shortage 
notification program'' could satisfy a vaccine manufacturer's 
obligation to notify FDA of a permanent discontinuance or an 
interruption in manufacturing under section 506C.
    As proposed, FDA is applying section 506C of the FD&C Act to all 
biological products, including recombinant therapeutic proteins, 
monoclonal antibody products, vaccines, allergenic products, plasma-
derived products and their recombinant analogs, blood or blood 
components, and cellular and gene therapy products. Shortages of 
biological products can have serious negative consequences for patients 
who rely on these products for their treatment. FDA anticipates that 
early notification of a permanent discontinuance or an interruption in 
the manufacturing of biological products will allow the Agency to 
address, prevent, or mitigate a shortage of these products, greatly 
benefiting the public health. In addition, we have determined that 
requiring manufacturers of biological products to notify FDA under this 
rule will not duplicate the existing reporting programs of which we are 
aware.
    a. Plasma-derived products and their recombinant analogs. Under 
Sec.  600.82(a), the requirements of section 506C of the FD&C Act apply 
to all biological products, including plasma products derived from 
human plasma protein and their recombinant analogs (referred to in this 
document as plasma-derived products and their recombinant analogs). As 
explained in the preamble to the proposed rule (78 FR 65904 at 65910), 
with respect to plasma-derived products and their recombinant analogs, 
FDA recognizes that the Plasma Protein Therapeutics Association (PPTA) 
has developed a voluntary data system that captures the distribution 
and supply of five plasma product groups in the United States: Plasma-
Derived Factor VIII, Recombinant Factor VIII, Immune Globulin (Ig), 
Albumin 5%, and Albumin 25%. The PPTA, in consultation with a third 
party, voluntarily submits a monthly report to FDA of aggregate 
distribution data for these five product groups. This information 
provides a picture of the total supply and distribution of these five 
products in any given month as compared to the last 12 months.
    FDA recognizes and greatly appreciates the efforts by PPTA to 
provide plasma product supply information to FDA and the public. 
However, as described in detail in the preamble to the proposed rule 
(78 FR 65904 at 65910), FDA concluded that it would benefit the public 
health for the Agency to receive direct notification under this rule 
from all manufacturers of these products. Because the PPTA program does 
not serve the same purpose as notification under this rule, including 
plasma-derived products and their recombinant analogs in this rule will 
not duplicate the PPTA system. FDA believes that including these 
products within the scope of the rule is essential to FDA's efforts to 
identify permanent discontinuances and interruptions in manufacturing 
of these products, and consequently, essential to our efforts to 
address, prevent, or mitigate shortages of these products.
    b. Vaccines. Under section 506C(i)(3)(B) of the FD&C Act, if FDA 
applies section 506C to vaccines, the Secretary must specifically 
consider whether the notification requirement may be satisfied by 
submitting a notification to CDC under CDC's ``vaccine shortage 
notification program.''
    CDC contracts with vaccine manufacturers as part of the Vaccines 
for Children (VFC) program.\8\ FDA recognizes that CDC includes 
language

[[Page 38919]]

in its contracts with vaccine manufacturers requiring the manufacturer 
to notify CDC of vaccine supply issues that could affect the 
manufacturer's ability to fulfill its contract with CDC.\9\ As 
explained in the preamble to the proposed rule (78 FR 65904 at 65910), 
only certain vaccines are included under the existing CDC program, and 
thus, only manufacturers of certain vaccines are obligated to provide 
notification of supply issues to CDC. Based on information from CDC, 
FDA estimates that approximately 30 percent of vaccines licensed in the 
United States are not subject to CDC notification.
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    \8\ The VFC program is a federally funded program that provides 
vaccines at no cost to children and adults who might not otherwise 
be vaccinated because of inability to pay. VFC was created by the 
Omnibus Budget Reconciliation Act of 1993 as a new entitlement 
program to be a required part of each state's Medicaid plan. CDC 
buys vaccines at a discount from the manufacturers and distributes 
them to awardees--i.e., State health departments and certain local 
and territorial public health Agencies--who in turn distribute them 
at no charge to those private physicians' offices and public health 
clinics registered as VFC providers. (See http://www.cdc.gov/vaccines/programs/vfc/index.html.)
    \9\ The Biomedical Advanced Research and Development Authority 
(BARDA), which is responsible for the procurement of certain 
vaccines related to medical countermeasures, also includes similar 
language in its procurement contracts. Contracts for the procurement 
of medical countermeasures against chemical, biological, nuclear, 
and radiological threat agents (e.g., smallpox and anthrax vaccines) 
are administered by BARDA, part of the Office of the Assistant 
Secretary for Preparedness and Response in the U.S. Department of 
Health and Human Services (HHS). (See http://www.hhs.gov/aspr.)
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    Moreover, even for the vaccines that are subject to CDC 
notification, the information collected is not adequate for purposes of 
this rule, because the existing CDC program does not require vaccine 
manufacturers to provide notice 6 months in advance of a permanent 
discontinuance or interruption in manufacturing. Early notice of 
permanent discontinuances and interruptions is critically important to 
the prevention of drug shortages. Although FDA and its HHS partners 
work together closely on vaccine supply issues, and the current 
framework for CDC notification is useful for contractual purposes, FDA 
has determined that including vaccines within the scope of this rule is 
necessary to fully support FDA's efforts to identify, address, prevent, 
or mitigate a vaccine shortage and would not be duplicative of existing 
notification systems.
    c. Blood or blood components for transfusion. The rule applies 
section 506C of the FD&C Act to blood or blood components, but in a 
more limited manner than for other biological products (Sec.  
600.82(a)(2)). The rule requires blood or blood component applicants 
(i.e., blood collection establishments subject to licensure) that 
manufacture a significant percentage of the U.S. blood supply to notify 
FDA of a permanent discontinuance or an interruption in manufacturing 
that is likely to lead to a ``significant disruption'' in the 
applicant's supply of blood or blood components. The rule is intended 
to require reporting of large-scale, permanent discontinuances, or 
interruptions in manufacturing of blood or blood components.
    FDA anticipates that the rule will ensure that FDA receives 
information essential to the Agency in preventing, mitigating, or 
addressing shortages of blood or blood components, while avoiding 
duplication with existing programs that monitor local and regional 
supplies of blood or blood components by ABO blood group.
    As explained in detail in the preamble to the proposed rule (78 FR 
65904 at 65911), we are aware of two significant efforts to monitor 
local and regional supplies of blood or blood components: (1) America's 
Blood Centers (ABC) and the Blood Availability and Safety Information 
System (BASIS) and (2) the Interorganizational Task Force on Domestic 
Disasters and Acts of Terrorism (Task Force), which is managed by the 
AABB (formerly the American Association of Blood Banks).
    The ABC and BASIS systems monitor the supply and demand of blood or 
blood components on a daily and weekly basis, and in the event of a 
national disaster. In other words, ABC and BASIS are tools for local 
blood centers and hospitals to track their day-to-day inventory of 
blood or blood components. Unlike the notifications required under this 
rule, ABC and BASIS are not designed to predict large-scale or 
nationwide disruptions in the supply of blood or blood components. 
Moreover, ABC and BASIS are voluntary systems, whereas the rule 
requires reporting.
    The Task Force was formed in January 2002 to help make certain that 
blood collection efforts resulting from domestic disasters and acts of 
terrorism are managed properly, and to deliver clear and consistent 
messages to the public regarding the status of the U.S. blood supply. 
The Task Force's efforts, although critical to public health, are 
focused on inventory management and are not intended to predict large-
scale disruptions in the supply of blood or blood components. The Task 
Force coordinates the movement of blood throughout the United States 
and appeals to the public for blood donations, but Task Force 
information is not sufficient for FDA in the context of predicting a 
permanent discontinuance or an interruption in manufacturing of these 
products that would have a large-scale impact.
    In short, although the information already available to FDA from 
the ABC, BASIS, and Task Force programs is useful, the existing 
frameworks are voluntary, do not result in a direct notification from 
an applicant to FDA, and only capture short-term, day-to-day supply and 
distribution information. In addition, in contrast to this rule, the 
existing systems are not equipped to predict large-scale, significant 
disruptions of blood or blood components. Accordingly, FDA has 
determined that including blood or blood components within the scope of 
this rule would benefit the public health, providing information that 
is essential to FDA's efforts to address shortages of these products.
    However, recognizing that the existing ABC, BASIS, and Task Force 
programs do provide certain information concerning the supply of blood 
or blood components, the reporting requirements apply only to 
applicants of blood or blood components that manufacture a significant 
percentage of the U.S. blood supply, and only to a permanent 
discontinuance of manufacture or an interruption in manufacturing that 
is likely to lead to a ``significant disruption'' in supply of that 
blood or blood component, as further described in sections III.A and 
III.C.1.
3. Scope of the Term ``Product''
    Under this rule, ``product'' refers to a specific strength, dosage 
form, and route of administration of a drug or biological product. For 
example, if Applicant X experiences an interruption in manufacturing of 
the 50-milligram (mg) strength of a drug product that would be subject 
to Sec.  314.81(b)(3)(iii), but the 100-mg strength continues to be 
manufactured without delay, under the rule, Applicant X must notify FDA 
of the interruption in manufacturing of the 50-mg strength if the 
interruption is likely to lead to a meaningful disruption in the 
applicant's supply of the 50-mg strength.

C. Notification of a Permanent Discontinuance or an Interruption in 
Manufacturing

1. Notification
    a. Permanent discontinuance. Section 506C of the FD&C Act requires 
manufacturers to notify FDA of a permanent discontinuance of 
manufacture of a covered drug. Sections 314.81(b)(3)(iii) and 600.82 
require the applicant to report all permanent discontinuances of 
covered drugs and biological products to FDA. For purposes of this 
rule, we interpret a permanent discontinuance to be a decision by the 
applicant for business or other reasons to cease manufacturing and 
distributing the product indefinitely.

[[Page 38920]]

    b. Interruption in manufacturing. In addition to permanent 
discontinuances, section 506C of the FD&C Act requires manufacturers to 
notify FDA of an interruption in manufacturing of a covered drug that 
is likely to lead to a meaningful disruption in supply of that drug in 
the United States. The statute defines ``meaningful disruption'' to 
mean a change in production that is reasonably likely to lead to a 
reduction in the supply of a drug by a manufacturer that is more than 
negligible and affects the ability of the manufacturer to fill orders 
or meet expected demand for its product; and does not include 
interruptions in manufacturing due to matters such as routine 
maintenance or insignificant changes in manufacturing so long as the 
manufacturer expects to resume operations in a short period of time.
    i. Drugs and biological products other than blood or blood 
components. Sections 314.81(b)(3)(iii)(a) and 600.82(a)(1) require the 
applicant for a product other than blood or blood components to report 
to FDA an interruption in manufacturing of the drug or biological 
product that is likely to lead to a meaningful disruption in supply of 
that drug or biological product in the United States. Sections 
314.81(b)(3)(iii)(f) and 600.82(f) adopt the statutory definition of 
``meaningful disruption in supply.''
    Consistent with the statutory definition of meaningful disruption, 
the rule requires an applicant to report an interruption in 
manufacturing likely to lead to a meaningful disruption in its own 
supply of a covered drug or biological product. In other words, when 
evaluating whether an interruption in manufacturing is reportable to 
FDA under the rule, rather than considering the potential impact of the 
interruption on the market as a whole, the relevant question 
(regardless of how large or small the applicant's market share may be) 
is whether the interruption is likely to lead to a reduction in the 
applicant's supply of a covered drug or biological product that is more 
than negligible, and affects the ability of the applicant to fill its 
own orders or meet the expected demand of its clients for the covered 
product. Consistent with the statute, the rule does not require an 
applicant to predict the market-wide impact of an interruption in its 
own manufacturing, which can be difficult to accurately assess and 
could lead to inconsistent interpretation of the regulation, less 
accurate predictions, and under- or overreporting.
    Under the rule, reportable discontinuances or interruptions in 
manufacturing of a covered drug or biological product include:
     A business decision to permanently discontinue manufacture 
of a covered drug or biological product.
     A delay in acquiring APIs or inactive ingredients that is 
likely to lead to a meaningful disruption in the applicant's supply of 
a covered drug or biological product while alternative API suppliers 
are located.
     Equipment failure or contamination affecting the quality 
of a covered drug or biological product that necessitates an 
interruption in manufacturing while the equipment is repaired or the 
contamination issue is addressed and that is likely to lead to a 
meaningful disruption in the applicant's supply of the product.
     Manufacturing shutdowns for maintenance or other routine 
matters, if the shutdown extends for longer than anticipated or 
otherwise is likely to lead to a meaningful disruption in the 
applicant's supply of a covered drug or biological product.
     A merger of firms or transfer of an application for a 
covered drug or biological product to a new firm, if the merger or 
transfer is likely to lead to a meaningful disruption in the 
applicant's supply of the product.
     An interruption in manufacturing (e.g., contamination of a 
manufacturing line) that in the applicant's view may not meaningfully 
disrupt the market-wide supply of the covered drug or biological 
product (for example, because the applicant holds only a small share of 
the market for the product), but that the applicant determines is 
likely to lead to a meaningful disruption in its own supply of the 
covered product.
    Conversely, an applicant is not required, under the rule, to notify 
FDA if an interruption in manufacturing is not likely to lead to a 
meaningful disruption in the applicant's supply of the drug or 
biological product. For example, FDA does not need to be notified in 
the following circumstances:
     A scheduled shutdown of an applicant's manufacturing 
facility for routine maintenance, if the shutdown is anticipated and 
planned for in advance and, therefore, is not expected to lead to a 
meaningful disruption in the applicant's supply of a covered drug or 
biological product.
     An unexpected power outage that results in an unscheduled 
interruption in manufacturing of a covered drug or biological product, 
if the applicant expects to resume normal operations within a 
relatively short timeframe and does not expect to experience a 
meaningful disruption in its supply of the covered drug or biological 
product.
    In either of these circumstances, if the interruption in 
manufacturing subsequently appears likely to lead to a meaningful 
disruption in the applicant's supply of the covered drug or biological 
product, then it would become a reportable interruption in 
manufacturing under the rule and the applicant must notify FDA.
    The list of examples described in this document is intended to 
assist industry in understanding what would (or would not) be required 
to be reported under amended section 506C of the FD&C Act, but the list 
is not exhaustive. The rule requires that any permanent discontinuance 
or any interruption in manufacturing that is likely to lead to a 
meaningful disruption in the applicant's supply of a covered drug or 
biological product be reported to FDA, even if not specifically 
described in this preamble.
    ii. Blood or blood components for transfusion. Section 600.82(a)(2) 
requires an applicant that manufactures a significant percentage of the 
U.S. blood supply to report to FDA an interruption in manufacturing of 
a blood or blood component that is likely to lead to a ``significant 
disruption'' in supply of that product in the United States. As 
explained in section III.A, FDA intends to consider an applicant that 
manufactures 10 percent or more of the U.S. blood supply to manufacture 
a significant percentage of the U.S. blood supply for purposes of this 
rule.\10\ Section 600.82(f) defines ``significant disruption'' as a 
change in production that is reasonably likely to lead to a reduction 
in the supply of blood or blood components by a manufacturer that 
substantially affects the ability of the manufacturer to fill orders or 
meet expected demand for its product; and does not include 
interruptions in manufacturing due to matters such as routine 
maintenance or insignificant changes in manufacturing so long as the 
manufacturer expects to resume operations in a short period of time. 
This definition of ``significant disruption'' closely follows, but is 
not identical to, the statutory and regulatory definition of 
``meaningful disruption.''
---------------------------------------------------------------------------

    \10\ Based on 2011 NCBUS data, this would be more than 1.5 
million units of whole blood annually or approximately 125,000 units 
per month. However, we note that the number may fluctuate year to 
year.
---------------------------------------------------------------------------

    For purposes of the rule, FDA intends to consider an interruption 
in manufacturing that leads to a reduction of 20 percent or more of an 
applicant's own supply of blood or blood components over a 1-month 
period to ``substantially affect'' the ability of the applicant to fill 
orders or meet expected demand; accordingly, such an

[[Page 38921]]

interruption would be considered a ``significant disruption'' in 
supply. Again, when determining whether an interruption in 
manufacturing is likely to lead to a significant disruption in supply, 
the blood or blood component applicant should not consider the market 
as a whole, but rather, should consider only its own supply of product.
    The definition of ``significant disruption'' (interpreted to mean 
affecting 20 percent or more of an individual applicant's supply over a 
1-month period) as applied to blood or blood components, in combination 
with limiting the rule only to applicants of blood or blood components 
that manufacture a significant percentage (10 percent or more) of the 
nation's blood supply, is intended to avoid duplication with existing 
programs to monitor the daily and weekly distribution of blood or blood 
components described in section III.B.2.c of this document and in the 
preamble to the proposed rule (78 FR 65904 at 65911). In general, 
existing programs maintained by ABC, BASIS, and the Task Force monitor 
and resolve temporary, local shortfalls of a particular ABO blood group 
or a particular blood component. Accordingly, the definition of 
``significant disruption'' is intended to capture events that are 
likely to precipitate large-scale disruptions in an applicant's blood 
supply and are unlikely to be identified and corrected by the existing 
ABC, BASIS, and Task Force programs. The additional limitation of the 
rule to applicants that manufacture a significant percentage of the 
nation's blood supply further ensures that reporting to FDA will not 
unnecessarily duplicate reporting to the ABC, BASIS, and Task Force 
systems, but still allows FDA to receive information that is essential 
to the Agency in preventing large-scale shortages of these products.
    Circumstances that trigger notification to FDA of a permanent 
discontinuance or an interruption in manufacturing of blood or blood 
components include the following examples. We recognize that, with the 
exception of the first example of a permanent discontinuance, the 
following interruptions are unlikely to be reasonably anticipated 6 
months in advance; they would be reportable as soon as practicable, but 
in no case later than 5 business days after the interruption in 
manufacturing occurs:
     A business decision by an applicant that manufactures 10 
percent or more of the nation's blood supply to permanently discontinue 
manufacture of blood or blood components;
     A computer system failure that causes an applicant of a 
blood establishment that collects 10 percent or more of the nation's 
blood supply to be unable to label blood for 2 weeks, resulting in a 20 
percent monthly shortfall of blood for that applicant;
     An issue with blood collection bags, such that they are 
unavailable, causing an applicant that manufactures 10 percent or more 
of the nation's blood supply to experience a 20 percent monthly 
shortfall in normal production for that applicant;
     An issue with apheresis collection devices that causes an 
applicant of a blood establishment that collects 10 percent or more of 
the nation's blood supply to be unable to collect platelets by 
apheresis, resulting in a 20 percent monthly shortfall in platelet 
supply for that applicant;
     An explosion or fire that damages a large testing 
laboratory that performs blood testing for an applicant that 
manufactures 10 percent or more of the nation's blood supply, resulting 
in a 20 percent monthly shortfall of blood or blood components for that 
applicant.
    Conversely, a covered blood or blood component applicant is not 
required under the rule to notify FDA if an interruption in 
manufacturing is not likely to lead to a significant disruption in the 
applicant's supply of blood or blood components. For example, FDA does 
not need to be notified if a covered blood or blood component applicant 
experiences a temporary drop in blood donations at one of its local 
blood donation centers, such that it is unable to fully supply its 
hospital customers with blood for several days, provided the donation 
center quickly returns to its normal donation and supply levels and the 
dip in blood donations is not likely to lead to a 20 percent decrease 
in the applicant's overall supply of blood over a 1-month period. We 
expect that this type of situation would be identified and resolved 
through the ABC, BASIS, and Task Force systems (e.g., these systems 
would identify the issue and locate temporary, alternative blood 
supplies for the applicant's customers). If such an event does lead to 
a significant disruption in a covered applicant's supply of blood or 
blood components, it must be reported to FDA under the final rule.
    Again, the list of examples described in this document is intended 
to assist industry in understanding what must be reported under amended 
section 506C of the FD&C Act, but the list is not exhaustive. The rule 
requires any permanent discontinuance or any interruption in 
manufacturing that is likely to lead to a significant disruption (as 
defined by the rule) in a covered applicant's supply of blood or blood 
components to be reported to FDA, even if not specifically discussed in 
this preamble.
2. Timing and Submission of Notification
    a. Timing of notification. Section 506C of the FD&C Act requires 
notification to FDA: (1) At least 6 months prior to the date of the 
permanent discontinuance or interruption in manufacturing or (2) if 6 
months' advance notice is not possible, as soon as practicable. 
Consistent with the statute, Sec. Sec.  314.81(b)(3)(iii)(b) and 
600.82(b) require an applicant to notify FDA of a permanent 
discontinuance or an interruption in manufacturing at least 6 months in 
advance of the date of the permanent discontinuance or interruption in 
manufacturing; or, if 6 months' advance notice is not possible, as soon 
as practicable thereafter, but in no case later than 5 business days 
after the permanent discontinuance or interruption in manufacturing 
occurs.
    The Agency's most powerful tool for addressing drug and biological 
product shortages is early notification, which provides lead time for 
FDA to work with manufacturers and other stakeholders to prevent a 
shortage or to mitigate the impact of an unavoidable shortage. As such, 
FDA expects that applicants would provide 6 months' advance notice 
whenever possible. In particular, FDA believes that an applicant will 
generally know of a permanent discontinuance at least 6 months in 
advance, and in that case, the applicant must provide notification of a 
permanent discontinuance to FDA at least 6 months in advance. We 
understand that an applicant may not reasonably be able to anticipate 6 
months in advance certain interruptions in manufacturing that are 
likely to lead to a meaningful disruption. For example, if an applicant 
discovers fungal contamination that requires an immediate, temporary 
shutdown of its manufacturing plant for a covered product, the 
applicant will not be able to provide FDA with 6 months' advance notice 
of the interruption in manufacturing. Instead, the rule requires that 
the applicant notify FDA ``as soon as practicable,'' but in no case 
more than 5 business days after the interruption in manufacturing 
occurs. In this example, the applicant must notify FDA as soon as it 
reasonably anticipates that an interruption in manufacturing caused by 
fungal contamination is likely to result in a meaningful disruption in 
supply of the applicant's product. The applicant should not wait until 
it or its

[[Page 38922]]

manufacturer begins rejecting or delaying fulfillment of orders for the 
product from available inventory (i.e., the applicant should not wait 
until the interruption in manufacturing actually begins to disrupt 
supply and affect patient access to the product).
    In our experience, even if it is not possible for an applicant to 
notify the Agency before a permanent discontinuance or an interruption 
in manufacturing occurs, it should generally be possible for the 
applicant to provide notice within a day or two, and it should always 
be possible for the applicant to notify the Agency no later than 5 days 
after the permanent discontinuance or interruption occurs, even in the 
event of a natural disaster or some other catastrophic incident. 
Accordingly, the 5-day provision represents a date certain after which 
FDA would be able to take action under section 506C(f) of the FD&C Act 
against an applicant for failure to comply with the notification 
requirements (see section III.C.6 for further discussion of the 
consequences of failure to notify FDA). Additionally, it is important 
to note that an applicant that could have notified the Agency before 5 
days had passed, but waited until the end of the 5-day period is in 
violation of the rule. Consistent with the statutory intent, whenever 
possible, applicants are required to provide us with advance notice, 
whether 6 months' advance notice, or ``as soon as practicable'' 
thereafter (e.g., 3 months' advance notice).
    b. Submission of notification. Sections 314.81(b)(3)(iii)(b) and 
600.82(b) require an applicant to notify FDA of a permanent 
discontinuance or an interruption in manufacturing electronically in a 
format FDA can process, review, and archive. Applicants must email 
notifications to drugshortages@fda.hhs.gov (for products regulated by 
CDER) or cbershortage@fda.hhs.gov (for products regulated by CBER). In 
the future, the Agency may consider creating an electronic notification 
portal linked to the Agency's internal drug shortages database to 
facilitate submission of these notifications. Unless and until this 
portal is created, however, email notifications will be used.
    c. Reduction in notification period for ``good cause.'' As 
described in the preamble to the proposed rule (78 FR 65904 at 65915), 
under the pre-FDASIA section 506C(b), a manufacturer could seek, and 
FDA could grant, a reduction in the required 6-month advance 
notification period for ``good cause.'' The regulation at Sec.  314.91 
implemented the pre-FDASIA section 506C(b). Because section 506C of the 
FD&C Act as amended by FDASIA does not include an option for formally 
seeking a reduction in the 6-month advance notification period based on 
``good cause,'' this rule eliminates Sec.  314.91 in its entirety.
3. Contents of the Notification
    Sections 314.81(b)(3)(iii)(c) and 600.82(c) require an applicant to 
include the following items in notifications submitted under section 
506C(a) of the FD&C Act:
     The name of the drug or biological product subject to the 
notification, including the NDC for the drug or biological product (or, 
for a biological product that does not have an NDC, an alternative 
standard for identification and labeling that has been recognized as 
acceptable by the Center Director);
     The name of the applicant of the drug or biological 
product;
     Whether the notification relates to a permanent 
discontinuance of the drug or biological product or an interruption in 
manufacturing of the drug or biological product;
     A description of the reason for the permanent 
discontinuance or interruption in manufacturing; and
     The estimated duration of the interruption in 
manufacturing.
    FDA requires applicants to include the minimum information listed 
in the initial notification to assist the Agency in complying with 
section 506E of the FD&C Act, which requires FDA to maintain a publicly 
available list of drugs in shortage, as described in section III.C.4. 
We recognize that the duration of an interruption in manufacturing can 
be difficult to accurately predict. Therefore the applicant should 
provide FDA with its best estimate of the expected duration of the 
interruption in manufacturing. If, after the initial notification is 
submitted, the estimated duration changes, the applicant should notify 
FDA of the new expected duration of the interruption in manufacturing 
so that FDA can respond appropriately. In addition, the applicant 
should include a detailed, factual description of the reason for the 
shortage in the notification to assist FDA in responding to the 
notification.
    Along with the required elements of the notification, applicants 
are encouraged to include any other information in the notification 
that may assist the Agency in working with the applicant to resolve the 
permanent discontinuance or interruption in manufacturing. This 
information could include the applicant's market share, inventory on 
hand or in distribution channels, allocation procedures and/or plans 
for releasing available product, copies of communications to patients 
and providers regarding the shortage (e.g., Dear Healthcare 
Professional letters), or initial proposals to prevent or mitigate the 
shortage. As appropriate, the Agency will also followup with the 
applicant after the notification is submitted to obtain additional 
information and to work with the applicant to facilitate resolution of 
any shortage or potential shortage.
4. Public Lists of Products in Shortage
    Section 506E of the FD&C Act requires FDA to maintain a publicly 
available list of drugs and biological products (if FDA applies section 
506C of the FD&C Act to biological products by regulation) that are 
determined by FDA to be in shortage, including providing the names and 
NDCs of the drugs, the name of each manufacturer of the drug, the 
reason(s) for the shortage, and the estimated duration of the shortage. 
Section 506C(h)(2) of the FD&C Act defines ``drug shortage'' to mean a 
period of time when the demand or projected demand for the drug within 
the United States exceeds the supply of the drug. For purposes of 
section 506E of the FD&C Act, under the rule, the ANDA, NDA, or BLA 
applicant is considered the manufacturer of an approved drug or 
biological product, even if the ANDA, NDA, or BLA applicant contracts 
that function out to another entity.
    Section 506E of the FD&C Act further requires FDA to include on the 
drug and biological product shortages lists the reason for the 
shortage, choosing from the following list of categories specified in 
the statute:
     Requirements relating to complying with current good 
manufacturing practices (CGMPs);
     Regulatory delay;
     Shortage of an active ingredient;
     Shortage of an inactive ingredient component;
     Discontinuation of the manufacture of the drug;
     Delay in shipping of the drug; and
     Demand increase in the drug.
    Consistent with the statute, and with FDA's current practice, under 
Sec. Sec.  310.306(c), 314.81(b)(3)(iii)(d), and 600.82(d), FDA will 
maintain publicly available lists of drugs and biological products that 
are determined by FDA to be in shortage, whether or not FDA has 
received a notification under this rule concerning the product in 
shortage. Sections 314.81(b)(3)(iii)(f) and 600.82(f) adopt the 
statutory definition of drug shortage (substituting ``biological 
product shortage'' for ``drug shortage'' in Sec.  600.82(f)). As 
specified in the rule, the

[[Page 38923]]

shortages lists will include the following required statutory elements 
for drugs or biological products in shortage: Names and NDCs (or the 
alternative standard for certain biological products) of the drugs or 
biological products, names of each applicant, reason for each shortage, 
and estimated duration of each shortage.
    If FDA has received a notification under the rule for the drug or 
biological product, FDA will consider the reason for the shortage 
supplied by the applicant in its notification and, where applicable, 
other relevant information before the Agency in determining how to 
categorize the reason for the shortage. Consistent with the statute, 
the Agency, not the applicant, is responsible for determining which 
categorical reason best fits a particular situation. In general, FDA 
intends to choose the categorical reason that best fits the applicant's 
supplied description. To facilitate FDA's determination of the 
categorical reason for the shortage, under the final rule we expect 
applicants to supply as many details and facts as possible concerning 
the reason for the permanent discontinuance or interruption in 
manufacturing when submitting a section 506C notification. This 
information will also assist FDA in responding quickly to the 
notification. If FDA has not received a notification under the rule, 
but becomes aware of a shortage through other means, FDA intends to 
consider information before the Agency when determining and choosing 
the reason for the shortage to be included on the public list.
    In addition to the list of statutory reasons for the shortage that 
FDA may choose from, the final rule also adds an eighth category, 
entitled ``Other reason.'' The Agency intends to choose ``Other 
reason'' only if none of the other listed reasons is applicable. For 
example, an interruption in manufacturing as a result of a natural 
disaster or other catastrophic loss would fall into the ``Other 
reason'' category. Moreover, although FDA may choose the ``Other 
reason'' category, the public shortages list will also include a brief 
summary of the reason for the shortage submitted by the applicant, thus 
providing additional information to the public on the cause of the 
shortage.
    The final rule codifies, consistent with FDASIA, FDA's current 
practice of maintaining public lists of drugs and biological products 
in shortage, available on FDA's Web site at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (for products regulated by CDER) 
and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (for products regulated by CBER).
    The list of CDER-regulated products includes six categories of 
information about each drug product on the list: Company (manufacturer 
of product and contact information); Product (name, strength, 
formulation, dosage, and NDC); Availability and Estimated Shortage 
Duration; Related Information (includes applicant's submitted 
description of reason for shortage); Shortage Reason (FDA-determined 
reason for the shortage, chosen from the list in Sec.  
314.81(b)(3)(iii)(d)); and Date Updated (last date FDA updated the 
information for that particular product). The list of CBER-regulated 
products includes similar information in fields for Product Name, 
Reason for Shortage, and Status.
5. Confidentiality and Disclosure
    In general, as required by sections 506C(c) and 506E of the FD&C 
Act, and as described in this document, FDA will publicly disclose, to 
the maximum extent possible, information on drug shortages, including 
information provided by applicants in a notification of a permanent 
discontinuance or an interruption in manufacturing. Sections 
314.81(b)(3)(iii)(d) and 600.82(d), however, specify that FDA may 
choose not to make information collected under the authority of the 
rule available to the public on the drug or biological product 
shortages lists or under its general obligation to disseminate drug 
shortage information under section 506C(c) of the FD&C Act if the 
Agency determines that disclosure of such information would adversely 
affect the public health (such as by increasing the possibility of 
hoarding or other disruption of the availability of the drug or 
biological product to patients). These provisions closely track the 
statutory language in sections 506C(c) and 506E(c)(3) of the FD&C Act.
    In addition, Sec. Sec.  310.306(c), 314.81(b)(3)(iii)(d), and 
600.82(d), as finalized, state that FDA will not provide on the public 
drug or biological product shortages lists or under section 506C(c) of 
the FD&C Act information that is protected by 18 U.S.C. 1905 or 5 
U.S.C. 552(b)(4), including trade secrets and commercial or financial 
information that is considered confidential or privileged under Sec.  
20.61. These provisions provide appropriate protection for commercial 
and trade secret information protected by other Federal law and are 
consistent with sections 506C(d) and 506E(c)(2) of the FD&C Act, which 
clarify that the information provisions in sections 506C and 506E do 
not alter or amend 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4). The final rule 
also implements a technical amendment to Sec.  20.100 to include a 
cross-reference to Sec. Sec.  310.306, 314.81, and 600.82. Section 
20.100 describes, by cross-reference to other regulations, the rules on 
public availability of certain specific categories of information.
6. Failure To Notify
    Consistent with section 506C(f) of the FD&C Act, Sec. Sec.  
310.306(b), 314.81(b)(iii)(3)(e), and 600.82(e), as finalized, provide 
that FDA will issue a noncompliance letter to an applicant (or, for a 
covered, unapproved drug, to a manufacturer) who fails to submit a 
section 506C notification as required under Sec. Sec.  
314.81(b)(iii)(3)(a) and 600.82(a) within the timeframe stated in 
Sec. Sec.  314.81(b)(iii)(3)(b) and 600.82(b). It is important to note 
that failure to notify FDA includes failure to timely notify FDA. For 
example, if FDA discovers that an applicant did not notify FDA of the 
permanent discontinuance of a covered drug or biological product 6 
months in advance, even though the applicant anticipated the permanent 
discontinuance 6 months in advance, FDA will issue a noncompliance 
letter. Similarly, if FDA determines that an applicant experienced a 
reportable interruption in manufacturing that it could not reasonably 
anticipate 6 months in advance, but the applicant failed to notify FDA 
``as soon as practicable,'' FDA will issue a noncompliance letter. 
Refer to section III.C.2.a for a discussion of the required timing for 
section 506C notifications.
    As required by section 506C(f) of the FD&C Act, the rule provides 
the applicant with 30 calendar days from the date of issuance of the 
noncompliance letter to respond to the letter. The applicant's response 
must set forth the basis for noncompliance and provide the required 
notification with the required information. Not later than 45 calendar 
days after the date of issuance of the noncompliance letter, FDA will 
make the letter and the applicant's response public, after appropriate 
redaction to protect any trade secret or confidential commercial 
information. FDA will not make the letter and the applicant's response 
public if FDA determines, based on the applicant's response, that the 
applicant had a reasonable basis for not notifying FDA as required.

IV. Comments on the Proposed Rule

    The Agency received submissions from 34 commenters, including 
public health associations, pharmaceutical industry, hospital groups, 
consumer

[[Page 38924]]

groups, and individuals. A summary of the comments contained in the 
submissions received and FDA's responses follow.
    To make it easier to identify comments and our responses, the word 
``Comment,'' in parentheses, appears before the comment's description, 
and the word ``Response,'' in parentheses, appears before our response. 
We have numbered each comment to help distinguish between different 
comments. Similar comments are grouped together under the same number. 
The number assigned to each comment is purely for organizational 
purposes and does not signify the comment's value or importance or the 
order in which comments were received.

A. Persons Subject to the Rule

    (Comment 1) One comment suggested that the notification requirement 
should be extended to API manufacturers. The comment stated that API 
manufacturers are further upstream in the drug development chain and 
that early warning of issues at this level, before they impact 
manufacturers formulating the drugs, would give FDA, other 
manufacturers of the drug, and programs more time to prepare and 
prevent shortages from affecting patients.
    (Response) FDA does not agree that the notification requirement 
should be applied to API manufacturers. While interruptions in API 
supply may lead to a meaningful disruption in supply of the finished 
drug or biological product, they do not always have this effect. 
Therefore, notification to FDA of disruption in API supply would be 
premature and would not provide information that the Agency can take 
definitive action on. FDA believes that the notification requirement, 
which is derived from section 506C of the FD&C Act, generally provides 
the Agency with adequate notice to allow the Agency to work with the 
applicant and other stakeholders to prevent a shortage. As explained in 
section III.A, however, it is important that the applicant establish a 
process with any relevant contract manufacturer, API supplier, or other 
non-applicant entity to ensure that the applicant complies with this 
rule.
    (Comment 2) One comment requested clarification on how a blood 
establishment will know if it is subject to the reporting requirements 
of the rule. The comment noted that the preamble to the proposed rule 
(78 FR 65904 at 65908) stated that FDA intends to consider a BLA-holder 
for blood or blood components to be a manufacturer of a significant 
percentage of the U.S. blood supply if the applicant manufactures 10 
percent or more of the U.S. blood supply. The comment explained that 
the National Blood Collection and Utilization Survey (NBCUS) supplies 
the best data available nationally on collection and utilization of 
blood in the United States, but notes that the survey is voluntary and 
does not occur on an annual basis. The comment stated that it is not 
possible for a BLA holder to know what percentage of the U.S. blood 
supply it is collecting. Accordingly, the comment recommended that FDA 
identify an annual whole blood collection number to be used as the 
threshold for reporting.
    (Response) FDA declines to identify an annual whole blood 
collection number to be used as a threshold for reporting because these 
numbers may fluctuate year to year. Because of their coordination with 
other BLA holders through the ABC, BASIS, and Task Force programs, we 
believe that BLA holders will generally be aware of whether they 
manufacture a significant percentage of the U.S. blood supply. 
Accordingly, we do not believe there will be significant uncertainty 
among BLA holders about whether they are subject to the notification 
requirements. If an applicant is unsure of whether it is subject to the 
notification requirements, we recommend that the applicant contact CBER 
at cbershortages@fda.hhs.gov.
    (Comment 3) One comment noted that the proposed rule did not 
discuss the effect of the notification provision on product allocation 
systems. The comment explained that products with inherently limited 
supply have been historically put on allocation systems by 
manufacturers to prioritize the allocation of these products. The 
comment explained that these allocation systems help manage and track 
product supplies, curb gray market distribution, and prevent price 
hikes. The comment stated that section 506(D)(d) of the FD&C Act 
directs FDA to establish a mechanism by which health care providers and 
other third party organizations may report to the Agency evidence of a 
drug shortage. The comment requested confirmation that a notification 
under section 506D(d) of the FD&C Act does not extend to situations 
where a receiving entity (e.g., a hospital) reaches its allocation 
limits.
    (Response) The comment is beyond the scope of this rulemaking. The 
final rule implements sections 506C and 506E of the FD&C Act by 
amending Sec. Sec.  20.100 and 314.81(b)(3)(iii) and adding new 
Sec. Sec.  310.306 and 600.82. The rule does not address section 506D 
of the FD&C Act. Consistent with section 506D(d), however, we do 
encourage patients, providers, pharmacists, and other non-applicants to 
communicate with FDA about potential shortages or disruptions in supply 
by email at drugshortages@fda.hhs.gov (for products regulated by CDER) 
or cbershortages@fda.hhs.gov (for products regulated by CBER), so that 
the Agency can take appropriate steps to address these situations.

B. Products Covered by the Rule

1. Prescription Drug and Biological Products That Are Life Supporting, 
Life Sustaining, or Intended for Use in the Prevention or Treatment of 
a Debilitating Disease or Condition
    (Comment 4) In the preamble to the proposed rule (78 FR 65904 at 
65909), FDA requested comment on the proposed definitions of ``life 
supporting or life sustaining'' and ``intended for use in the 
prevention or treatment of a debilitating disease or condition'' and in 
particular, whether the definitions might lead to ``over-
notification.'' The majority of commenters supported the proposed 
definitions and agreed that they are consistent with current 
understanding of these terms. Some commenters noted that there might be 
the potential for over-notification but agreed that more information, 
rather than less, will enhance FDA's ability to prevent drug and 
biological product shortages. One comment stated that the definitions 
could lead to over-notification if they are broadly interpreted but 
noted that it is difficult to predict whether over-notification will 
actually occur. The comment suggested that within 1 year of 
implementation of the final rule, FDA can assess whether 
overnotification has occurred and can revise the draft guidance for 
industry entitled ``Notification to FDA of Issues that May Result in a 
Prescription Drug or Biological Product Shortage'' to include 
additional examples of products that are or are not likely to fall 
within the scope of products subject to the notification provision.
    (Response) FDA appreciates the commenters' input. We continue to 
believe that the proposed definitions provide sufficient clarity 
without overly restricting the categories of products subject to the 
rule. We have therefore finalized the definitions that were proposed 
and believe that these definitions will result in appropriate 
notifications under the rule. If, however, FDA finds that over-
notification has occurred, the Agency may consider further 
clarification in guidance or by other suitable means.

[[Page 38925]]

    (Comment 5) Three comments stated that the proposed definitions 
were overly broad, potentially encompassing the majority of approved 
drug and biological products, and may be subject to inconsistent 
interpretation. Two comments recommended using definitions based on the 
definitions of ``immediately life-threatening disease or condition'' 
and ``serious disease or condition'' in Sec.  312.300. One of those 
comments specifically proposed the following definitions:
     ``A life supporting or life sustaining drug product means 
a drug product that is essential to, or yields information that is 
essential to, the restoration or continuation of a bodily function 
associated with a stage of disease in which there is a reasonable 
likelihood that death will occur within a matter of months or in which 
premature death is likely without early treatment.''
    and
     ``A debilitating disease or condition means a serious 
disease or condition associated with morbidity that has a substantial 
impact on day-to-day functioning. Short-lived and self-limiting 
morbidity will usually not be sufficient, but the morbidity need not be 
irreversible, provided it is persistent or recurrent. Whether a disease 
or condition is serious is a matter of clinical judgment, based on its 
impact on such factors as survival, day-to-day functioning, or the 
likelihood that the disease, if left untreated, will progress from a 
less severe condition to a more serious one.''
    (Response) FDA does not believe it is appropriate to incorporate 
the comment's proposed definitions or alternative definitions based on 
the definitions set forth in Sec.  312.300. As explained in section 
III.B.1, under Sec. Sec.  314.81(b)(3)(iii)(f) and 600.82(f) of this 
final rule, FDA equates ``debilitating disease or condition'' with 
``serious disease or condition,'' and we have defined ``debilitating 
disease or condition'' according to the definition of ``serious disease 
or condition'' found in Sec.  312.300. In the Agency's view, the 
definitions suggested in the comment would be too restrictive and could 
exclude certain products, such as anesthetic products, that are 
critical to patient care and should appropriately be considered ``life 
supporting or life sustaining'' or ``intended for use in the prevention 
or treatment of a debilitating disease or condition.'' As noted in the 
previous response, FDA believes that the definitions in this final rule 
provide sufficient clarity without overly restricting the categories of 
products subject to the rule. If, following implementation of the rule, 
it appears that further clarification is necessary, FDA will consider 
what type of clarification may be beneficial and take appropriate 
steps.
    (Comment 6) Three comments suggested that FDA should consider 
providing a list, in guidance or otherwise, of examples of drug 
products or classes of drug products that are likely to meet the 
definitions of ``life supporting or life sustaining'' or ``intended for 
use in the prevention or treatment of a debilitating disease or 
condition.'' The commenters suggested that such a list would provide 
greater clarity and facilitate compliance with the rule.
    (Response) FDA does not believe it is appropriate to provide a list 
of products that are likely to meet the definitions of ``life 
supporting or life sustaining'' or ``intended for use in the prevention 
or treatment of a debilitating disease or condition.'' Such a list 
would be difficult to maintain and keep up to date as products come off 
the market and new products enter the market. We are also concerned 
that applicants and the public may misinterpret the list as an 
exhaustive list of all products that would be subject to the 
notification requirement, rather than as examples of drug products or 
classes of drug products that are likely to meet the definitions.
    If an applicant is uncertain whether a particular discontinuance or 
interruption in manufacturing of a drug or biological product should be 
reported to FDA, we encourage the applicant to proceed with 
notification. It is important to note that, under section 1001(b) of 
FDASIA, submission of a notification will not be construed as: (1) An 
admission that any product that is the subject of the notification 
violates any provision of the FD&C Act or (2) evidence of an intention 
to promote or market the product for an unapproved use or indication.
    (Comment 7) One comment requested that FDA recognize attention-
deficit hyperactivity disorder (ADHD) as an example of a debilitating 
condition. The comment stated that FDA could do so by adding to the 
definition in the final rule a list of some debilitating diseases and 
conditions and including ADHD in that list.
    (Response) FDA has recognized ADHD as an example of a debilitating 
condition. We note further that when products used to treat ADHD have 
gone into shortage, they have been included on FDA's drug shortages Web 
site. However, FDA declines to add a list of examples of debilitating 
conditions to the rule.
    (Comment 8) One comment requested clarification that drugs used to 
treat a ``debilitating disease or condition'' include sedatives, 
anesthetics, analgesics, and anti-inflammatory drugs.
    (Response) FDA has considered sedatives, anesthetics, analgesics, 
and anti-inflammatory drugs to be drugs that are intended for use in 
the prevention or treatment of a debilitating disease or condition.
    (Comment 9) One comment suggested that the rule be modified to give 
FDA the option of including a statement in the approval letter for new 
NDAs, ANDAs, or BLAs indicating that the product is covered by the 
rule. The comment noted that this type of statement about the product's 
status would provide clarity and could be beneficial, especially to 
applicants entering the U.S. market for the first time.
    (Response) FDA understands that including a statement in the 
approval letter that the product is covered by this rule would clarify 
that particular product's status. The Agency is concerned, however, 
that such action may create confusion about the status of other 
already-approved products where the approval letter does not include a 
statement regarding notification under this rule. Applicants and other 
stakeholders may believe that the notification requirement only applies 
with respect to products whose approval letter contains a statement 
about notification under this rule. Therefore, FDA does not think it 
would be appropriate to add a provision to the rule as suggested by the 
comment.
    (Comment 10) One comment requested clarification that the 
definition of ``medically necessary'' in the drug shortage MAPP solely 
relates to the allocation of internal Agency staffing and resources and 
that it has no bearing on the scope of products subject to notification 
under the proposed rule or FDA's determination of an actual shortage 
and public notification of a shortage.
    (Response) As explained in section IV.B.1 of this document and in 
the preamble to the proposed rule, under this rule, an applicant is 
required to notify FDA of a permanent discontinuance or an interruption 
in manufacturing of a drug or biological product that is life 
supporting, life sustaining, or intended for use in the prevention or 
treatment of debilitating disease or condition, whether or not the 
product is considered medically necessary under the MAPP. Under the 
MAPP, FDA uses the definition of medically necessary to prioritize the 
Agency's response to specific shortages

[[Page 38926]]

or potential shortages and to allocate resources appropriately.
    (Comment 11) One comment expressed support for the inclusion of 
prescription drug products marketed without an approved NDA or ANDA and 
noted that such products are often critical to patient care.
    (Response) FDA agrees that prescription drug products marketed 
without approved applications are important in patient care and 
accordingly Sec.  310.306 is being finalized as proposed to ensure that 
the Agency is notified of a permanent discontinuance or an interruption 
in manufacturing of such products, as appropriate.
    (Comment 12) Three comments raised questions about off-label uses. 
One comment requested clarification that off-label indications are not 
included within the scope of ``marketed unapproved prescription 
drugs.'' Two comments noted that many prescription drug products used 
to treat children and nearly all prescription drug products used to 
treat neonates are not labeled for use in those populations. 
Accordingly, those two comments stated that the rule should require 
notification based on off-label uses in addition to the uses in the 
labeling.
    (Response) Off-label uses of drug and biological products are not 
included within the scope of ``marketed unapproved prescription 
drugs.'' FDA is not requiring applicants to consider off-label uses 
when determining whether a product is a covered product for purposes of 
the notification requirement in section 506C of the FD&C Act and 
implemented in this rule. The Agency understands that off-label uses 
can, in certain circumstances, be an important part of patient care. In 
fact, as explained in the MAPP on drug shortages (CDER MAPP 4190.1 Rev. 
2), FDA considers off-label uses when classifying products as medically 
necessary for purposes of prioritization. However, off-label uses are 
based on a practitioner's professional judgment about what will benefit 
an individual patient, and we do not believe it would be reasonable to 
expect applicants to take account of individual practitioners' 
therapeutic decisionmaking in assessing whether their products are 
subject to the notification requirement. We note that in many cases, 
though, products that would be covered by the rule if it applied based 
on an off-label use may nevertheless be covered products based on a 
labeled use, in which case the applicant would be subject to the 
notification requirement for that product.
2. Biological Products
    (Comment 13) Many comments strongly supported applying section 506C 
of the FD&C Act to biological products. These comments expressed the 
view that early notification of a permanent discontinuance or an 
interruption in manufacturing of biological products would benefit the 
public health by facilitating prompt action on FDA's part to address, 
prevent, or mitigate a shortage of these products.
    (Response) FDA appreciates these comments and agrees that extending 
the notification requirement to biological products will benefit the 
public health. Therefore, consistent with section 506C(i)(3), the 
Agency is finalizing Sec.  600.82 as proposed.
    (Comment 14) Two comments requested that the Agency make clear that 
biosimilars are subject to the provisions of section 506C of the FD&C 
Act. The comments stated that while the approval process for 
biosimilars is still under development, it is important that such 
products be included in the requirements of the final rule.
    (Response) This rule applies to prescription biological products 
licensed under section 351 of the PHS Act,\11\ including prescription 
biosimilar biological products licensed under section 351(k) of the PHS 
Act, that are life supporting, life sustaining, or intended for use in 
the prevention or treatment of a debilitating disease or condition, 
including any such product used in emergency medical care or during 
surgery, and excluding radiopharmaceutical products.
---------------------------------------------------------------------------

    \11\ As noted in footnote 1 to the Executive Summary, the term 
``biological product'' refers to a biological product licensed under 
section 351 of the PHS Act, other than a biological product that 
also meets the definition of a device in section 201(h) of the FD&C 
Act.
---------------------------------------------------------------------------

    (Comment 15) One comment expressed support for the inclusion of 
blood or blood components for transfusion but requested clarification 
on how FDA will determine which blood or blood components would be 
exempt from the rule and how FDA plans to address shortages of products 
determined to be exempt. In particular, the comment sought 
clarification on whether the rule would apply to reagents used to 
cross-match platelets for transfusion. The comment stated that there 
have been shortages of these reagents recently, which has impacted 
patient care.
    (Response) As explained in section III.B.2.c, the notification 
requirement applies only to applicants of blood or blood components for 
transfusion that manufacture a significant percentage of the U.S. blood 
supply, and only when there is a permanent discontinuance of 
manufacture or an interruption in manufacturing that is likely to lead 
to a ``significant disruption'' in supply of that blood or blood 
component. As noted in footnote 1 in the Executive Summary, the rule 
does not apply to biological products that meet the definition of a 
device in section 201(h) of the FD&C Act. Accordingly, this rule does 
not apply to reagents or other products that CBER regulates as devices, 
such as products intended for screening or confirmatory clinical 
laboratory testing associated with blood banking practices and other 
testing procedures (e.g., blood typing and compatibility testing).
    (Comment 16) Two comments stated that blood and blood components 
should not be included in the rule. The comments cited the current 
systems described in the preamble to the proposed rule (78 FR 65904 at 
65911) that monitor local and regional supplies of blood or blood 
components and coordinate during domestic disasters. The comments noted 
that blood and blood components do not have a history of shortages and 
stated that given the existing reporting systems and acknowledged 
successful record of planning activities in the blood community, 
coordination among the major blood organizations, and cooperation with 
FDA and HHS during and following disasters, it is not necessary to add 
another layer of reporting that is unlikely to provide additional 
security.
    (Response) As explained in the preamble to the proposed rule (75 FR 
65904 at 65911) and in section III.B.2.c, FDA agrees that the 
information available from ABC and BASIS and the efforts by the Task 
Force are critical to public health, and the Agency appreciates the 
willingness of applicants to coordinate. However, there are limitations 
to these existing systems. These systems are voluntary, they do not 
result in a direct notification from an applicant to FDA, and they only 
capture short-term, day-to-day supply and distribution information. In 
addition, the existing systems are not equipped to predict large-scale, 
significant disruptions of blood or blood components. We believe that 
including blood and blood components in the final rule will allow FDA 
to anticipate large-scale, significant disruptions of blood or blood 
components and take appropriate action. Accordingly, FDA has determined 
that including blood and blood components within the scope of this rule 
will benefit the public health

[[Page 38927]]

by ensuring that the Agency is provided with information essential to 
FDA's efforts to address shortages of these products without 
duplicating existing programs.
    (Comment 17) One comment stated that cellular and gene therapy 
products should not be included in the rule. The comment stated these 
are relatively new products and that the notification requirements are 
not necessary for them. The comment noted that BLA holders should be 
reporting to FDA, at least annually, what products are being 
manufactured under the license, and if an applicant is experiencing 
difficulty manufacturing a product, the applicant can communicate with 
FDA. The comment stated further that it is difficult to understand the 
``meaningful'' process FDA would initiate if a report is received from 
a cellular or gene therapy manufacturer, and recommended that if 
cellular and gene therapy products are included in the final rule, FDA 
should provide a specific guidance document addressing these products.
    (Response) FDA does not agree that cellular and gene therapy 
products should be excluded from the rule, nor do we agree that 
periodic distribution reporting or voluntary communication with FDA 
regarding manufacturing difficulties are adequate to allow the Agency 
to address shortages of cellular and gene therapy products. Shortages 
of biological products can have serious health consequences for 
patients who rely on these products for their treatment. Early 
notification of a permanent discontinuance or an interruption in the 
manufacturing of biological products is crucial for allowing FDA to 
take steps to prevent, or mitigate a shortage of these products.
    The required distribution reports referred to in the comment do not 
provide sufficient notice for FDA to anticipate a shortage or take 
appropriate action to address a shortage. As explained in the preamble 
to the proposed rule (78 FR 65904 at 65911), under Sec.  600.81, 
applicants are required to submit to CBER or CDER information about the 
quantity of product distributed under the license, including the 
quantity of product distributed to distributors. As part of the safety 
reporting requirement, manufacturers provide distribution data to FDA 
every 6 months or at other intervals as may be required by FDA. 
Although distribution reports submitted by applicants are helpful in 
the analysis of safety reporting data, these reports do not include 
information about a permanent discontinuance or an interruption of the 
manufacture of a biological product that is likely to lead to a 
meaningful disruption in the supply of that product. In addition, any 
distribution data received from the applicant at 6-month intervals may 
not be current. Accordingly, FDA has determined that including cellular 
and gene therapy products within the scope of this rule would benefit 
the public health by ensuring that FDA is provided with information 
that is essential to Agency's efforts to address shortages of these 
products. If, following implementation of the rule, it appears that 
guidance or further clarification is necessary for cellular and gene 
therapy products, FDA will consider what type of guidance may be 
beneficial and take appropriate steps in accordance with good guidance 
practices set out in 21 CFR 10.115.
    (Comment 18) Two comments recommended that the rule not be applied 
to vaccines. The comments stated that, in response to the unique nature 
of vaccines, the CDC has successfully partnered with vaccine applicants 
to reduce, if not eliminate completely, impacts to public health that 
may arise due to a supply shortage. The comments stated that CDC 
continues to be in the best position to monitor and manage vaccine 
supply. The comments suggested that the CDC should continue to act as a 
confidential facilitator of critical supply information that is 
provided by applicants or manufacturers, to maintain these data as 
proprietary and confidential, and to allow CDC to use the information 
so that other applicants or manufacturers can fill the gap in the event 
of an imminent shortage. In addition, the comments noted that, for over 
a decade, the vaccine industry has voluntarily strived to provide FDA 
with the requested minimum 6-month notice when making a determination 
to discontinue production of a particular vaccine, where such a 
decision was foreseeable.
    Alternatively, the comments proposed that FDA consider limiting the 
scope of the proposed rule to cover only non-VFC vaccines since there 
already are effective notification and distribution systems in place 
under the VFC program. The comments noted that CDC maintains a 
stockpile of VFC vaccines as part of its vaccine shortage notification 
program. Due to the CDC's regular collaboration with vaccine 
manufacturers, this program has proven highly successful in mitigating 
or completely eliminating supply disruptions.
    (Response) FDA does not agree with the commenters' suggestion that 
the rule should not apply to vaccines or, in the alternative, should 
only apply to non-VFC vaccines. FDA recognizes that CDC includes 
language in its contracts with vaccine manufacturers requiring the 
manufacturer to notify CDC of vaccine supply issues that could affect 
the manufacturer's ability to fulfill its contract with CDC. FDA does 
not intend this rule to disrupt the contractual process and procedures 
that exist between manufacturers and CDC. However, as explained in the 
preamble to the proposed rule (78 FR 65904 at 65910), approximately 30 
percent of vaccines licensed in the United States are not subject to 
CDC notification, including vaccines for rabies, yellow fever, and 
typhoid. Even for the vaccines that are subject to CDC notification, 
the information collected by CDC is not adequate for purposes of this 
rule. The existing CDC program does not require vaccine manufacturers 
to provide notice 6 months in advance of a permanent discontinuance or 
interruption in manufacturing. Early notice of permanent 
discontinuances and interruptions is critically important to prevention 
of drug and biological product shortages. Although FDA and its HHS 
partners work together on vaccine supply issues, FDA believes that 
including vaccines within the scope of this rule is essential to fully 
support FDA's efforts to identify, address, prevent, or mitigate a 
vaccine shortage.
    (Comment 19) Two comments noted that by design, influenza vaccine 
is a seasonal product and consequently, is unavailable for a 
significant portion of each year. The comments stated that for this 
reason, both seasonal influenza and pandemic influenza vaccines should 
not be covered by the rule.
    (Response) We acknowledge that some vaccines, such as those for 
influenza, are seasonal products by design and consequently may be 
unavailable for a significant portion of the year. It is important to 
note that ``meaningful disruption'' is defined as a ``reduction in the 
supply of a drug . . . that is more than negligible and affects the 
ability of the manufacturer to fill orders or meet expected demand for 
its product.'' In the case of a seasonal product, we anticipate that 
demand would decrease during the off-season; therefore, we would not 
expect that an interruption in manufacture of a seasonal product would 
be likely to lead to a meaningful disruption in the off-season. 
Accordingly, we decline to exempt vaccines intended for seasonal and 
pandemic use. We believe shortages of biological products, including 
seasonal influenza vaccines, can have serious health consequences for 
patients who rely on these products. Early notification of a permanent 
discontinuance or an interruption in the

[[Page 38928]]

manufacturing of these products will allow FDA to promptly take steps 
to prevent or mitigate a shortage of these products that could 
otherwise result in delayed patient access.
3. Scope of the Term ``Product''
    (Comment 20) Two comments noted that the proposed rule would apply 
individually to all strengths, dosage forms, or routes of 
administration for a given product regardless of the supply status for 
other presentations and dosages of the same product. The commenters 
suggested that the rule should allow greater flexibility and should not 
apply to a product if an alternate presentation of the same therapeutic 
product is available.\12\
---------------------------------------------------------------------------

    \12\ We understand the comment to mean that the rule should not 
apply to a particular applicant if that applicant has available the 
same product in a different presentation, e.g., a different 
strength.
---------------------------------------------------------------------------

    (Response) FDA does not agree. As we explained in the preamble to 
the proposed rule (78 FR 65904 at 65912), we understand that the 
permanent discontinuance or interruption in manufacturing of a specific 
strength, dosage form, or route of administration can have a 
significant impact on the targeted needs of particular patients. The 
Agency strives to ensure the availability of appropriate treatment 
options for patients. We also note that shortages of a specific 
strength, dosage form, or route of administration may lead to a 
shortage of another strength, dosage form, or route of administration, 
thereby exacerbating difficulties in obtaining the product. 
Furthermore, as explained in other comments on the proposed rule 
(available in Docket No. FDA-2011-N-0898), requiring notification based 
on the status of each strength, dosage form, and route of 
administration helps to ensure that patients and their health care 
providers have the most accurate information about potential shortages, 
and can make treatment decisions accordingly.
    If the applicant has available an alternate presentation of the 
same product, the applicant should include that information in the 
notification as a proposal to mitigate the shortage.
    (Comment 21) One comment requested confirmation that notification 
is not required when there is a shortage of a particular ``count'' of 
product but overall the quantity of that product is not in shortage 
(e.g., a manufacturer is in short supply of a 50-count bottle of 10-mg 
pills, but there are sufficient numbers of 25-count bottles of 10-mg 
pills to meet patient need).
    (Response) FDA would not require notification in the situation 
described in the example provided.

C. Notification of a Permanent Discontinuance or an Interruption in 
Manufacturing

1. Notification
    (Comment 22) One comment expressed concern about the notification 
requirement as applied to blood or blood components. The comment cited 
the proposed rule (78 FR 65904 at 65913) and stated that monthly 
reporting of a decrease in any blood component produced by an affected 
BLA holder is overly burdensome and would result in reports that are 
meaningless. The comment recommended that FDA provide information and 
recommendations in a draft guidance to more fully explain the goals of 
this particular data collection.
    (Response) The rule requires the notification of a permanent 
discontinuance or an interruption in manufacturing of blood or blood 
components that is likely to lead to a significant disruption in supply 
of the product in the United States. FDA intends to consider an 
interruption in manufacturing that leads to a reduction of 20 percent 
or more of an applicant's own supply of blood or blood components over 
a 1-month period to ``substantially affect'' the ability of the 
applicant to fill orders or meet expected demand. Such an interruption 
would be considered a significant disruption in supply. The rule does 
not require manufacturers to submit or report monthly data. The rule, 
as applied to BLA holders for blood or blood components for 
transfusion, is intended to capture events that are likely to 
precipitate large-scale disruptions in an applicant's blood supply.
    (Comment 23) One comment expressed concern that the requirement 
that applicants report an ``interruption in manufacturing'' that is 
likely to cause a disruption in the manufacturer's own supply of a drug 
or biological product could keep important information from being 
reported to FDA. The comment explained that a manufacturer that is not 
experiencing ``an interruption in manufacturing,'' but rather is 
experiencing a lack of available product due to an increase in demand 
would not be required to notify the Agency. The comment suggested that 
FDA consider expanding the notification requirement to include those 
applicants experiencing a shortage in supply due to an increase in 
product demand.
    (Response) FDA agrees that notification by an applicant lacking 
available product because of an increase in demand, and not because of 
an interruption in manufacturing, could be helpful in anticipating and 
addressing potential shortages. However, such a notification 
requirement is beyond the scope of section 506C of the FD&C Act 
implemented by the final rule. FDA does encourage applicants to 
communicate with FDA if there is an increase in demand that the 
applicant is not able to meet. We also note that if an applicant 
experiences an increase in demand because of another applicant's 
permanent discontinuance or interruption in manufacturing, FDA would 
expect to receive notification about the situation from the applicant 
that has experienced the discontinuance or interruption.
    (Comment 24) Two comments recommended specific modifications to the 
definition of ``meaningful disruption,'' believing it to be unclear and 
potentially subject to inconsistent interpretation. First, the comments 
stated that terms within the definition, such as ``reasonably likely,'' 
``more than negligible,'' and ``short period'' are insufficiently 
precise and recommended that the terms be removed from the definition. 
Second, the comments stated that, under the definition, applicants 
would be required to notify FDA if any products are under allocation or 
the demand for the product exceeds the available supply. Accordingly, 
the comments suggested adding language to the definition with the 
clarification that ``meaningful disruption'' means that the adverse 
impact to supply is unable to be remediated or minimized through 
allocation or other means of prioritization. Last, the comments noted 
that many factors could potentially affect the ability of applicants to 
fill orders, including some that are not within an applicant's control. 
The comments noted that applicants do not ultimately determine, nor can 
they in all cases accurately predict, volumes of orders or product 
demand. One of the comments accordingly recommended that FDA consider 
including language to clarify that the definition of ``meaningful 
disruption'' is intended to reflect situations in which the 
availability of a product to patients would be impacted. The comment 
suggested that the rule should clarify whose orders the applicant needs 
to be able to fill, in order to distinguish between the temporary 
inability to fulfill an order to a wholesaler, as opposed to the 
inability of a patient to obtain a prescription or receive appropriate 
therapy.
    (Response) The final rule is being issued to implement sections 
506C and 506E of the FD&C Act, consistent with section 506C(i). Section 
506C(h) defines ``meaningful disruption'' as ``a change in production 
that is reasonably likely

[[Page 38929]]

to lead to a reduction in the supply of a drug by a manufacturer that 
is more than negligible and affects the ability of the manufacturer to 
fill orders or meet expected demand for its product'' and that ``does 
not include interruptions in manufacturing due to matters such as 
routine maintenance or insignificant changes in manufacturing so long 
as the manufacturer expects to resume operations in a short period of 
time.'' The final rule adopts the statutory definition. In our view, 
the language used in the statute provides flexibility to accommodate 
the wide variety of circumstances that may result in drug or biological 
product shortages. If there is any uncertainty about whether a 
particular circumstance must be reported to FDA under the rule, we 
encourage applicants to submit a notification. Early notification is 
FDA's best tool for addressing shortages. Moreover, submission of a 
notification will not be construed as: (1) An admission that any 
product that is the subject of the notification violates any provision 
of the FD&C Act or (2) as evidence of an intention to promote or market 
the product for an unapproved use or indication.
    (Comment 25) One comment noted that the preamble to the proposed 
rule (78 FR 65904 at 65912 and 65913) provides a number of examples of 
reportable discontinuances or interruptions in manufacturing of a 
covered drug or biological product. The comment stated that not all of 
the examples would result in a shortage of product to patients and may 
result in industry ``over-reporting'' events to the Agency. 
Accordingly, the comment requested that FDA further clarify the 
requisite link between the examples provided and an actual ``meaningful 
disruption'' in supply.
    (Response) The list of examples provided in the preamble to the 
proposed rule are intended to assist applicants in understanding what 
must be reported under section 506C of the FD&C Act. As implemented by 
the final rule, section 506C requires that applicants notify FDA of a 
permanent discontinuance in the manufacture of a covered drug or 
biological product or an interruption of the manufacture of the drug or 
biological product that is likely to lead to a meaningful disruption in 
the supply of that product in the United States, and the reasons for 
such discontinuance or interruption. The list of examples is not 
intended to include only situations that will necessarily result in a 
meaningful disruption in supply. The list includes examples of events 
(i.e., permanent discontinuance and interruption in manufacturing) that 
are likely to lead to a meaningful disruption in supply and therefore 
must be reported to the Agency.
    (Comment 26) One comment suggested that FDA amend the rule to 
require blood component manufacturers to report a decrease in donations 
when it is due to their own decision to close donation sites versus the 
natural ebb and flow of blood donation cycles. The comment stated that 
companies have the ability to create shortages with the purpose of 
increasing prices by closing donation sites.
    (Response) FDA does not agree the suggested change is necessary or 
appropriate. As explained in the preamble to the proposed rule (78 FR 
65904 at 65913), FDA need not be notified if a covered blood or blood 
component applicant experiences a temporary drop in blood donations at 
one of its local blood donation centers, such that it is unable to 
fully supply its hospital customers with blood for several days, 
provided the donation center quickly returns to its normal donation and 
supply levels and the dip in blood donations is not likely to lead to a 
20 percent decrease in the applicant's overall supply of blood over a 
1-month period. We expect that this type of situation would be 
identified and resolved through the existing programs that coordinate 
local and regional supplies of blood or blood components (e.g., these 
systems would identify the issue and locate temporary, alternative 
blood supplies for the applicant's customers). If such an event does 
lead to a significant disruption in a covered applicant's supply of 
blood or blood components, it would need to be reported to FDA under 
this rule.
    (Comment 27) One comment noted that some of the quality issues 
subject to notification under the rule also would be subject to 
reporting under Field Alert Reports for drugs and Biological Product 
Deviation Reports for biological products. In an effort to avoid dual 
reporting requirements, the comment suggested that FDA attempt to 
coordinate these reports and the Agency's followup in order to minimize 
the burden on both FDA and applicants.
    (Response) FDA recognizes that some quality issues that result in 
interruptions in manufacturing subject to this rule could also be 
subject to reporting under Field Alert Reports (FARs) for drugs and 
Biological Product Deviation Reports (BPDRs) for biological products. 
However, FARs and BPDRs are not supply reporting programs and do not 
serve the same purpose as notification under this rule. Applicants with 
approved NDAs and ANDAs are required to submit FARs to FDA if they find 
any significant problems with an approved drug; the purpose of the 
Field Alert Program is to quickly identify drug products that pose 
potential safety threats. Similarly, BPDRs are used by biological 
product manufacturers to report biological product deviations that may 
affect the safety, purity, or potency of a distributed product. 
Problems reported through FARs and BPDRs may not lead to a shortage. 
Moreover, we note that the timing of these reports and the information 
provided in them may not be adequate for FDA to address potential 
shortages. Therefore, we have determined that requiring manufacturers 
of drugs and biological products to notify FDA under this rule will not 
duplicate existing reporting programs and will provide the Agency with 
necessary information and lead time to take appropriate action to 
prevent or mitigate a shortage.
    (Comment 28) One comment proposed that additional factors be taken 
into consideration and used as ``filters'' when manufacturers report 
drug and biologics shortages in order to limit the reporting of 
potential supply chain disruptions that are not ``true drug shortage'' 
events. The comment stated that these factors might include market 
dynamics and duration of supply chain shortage. With regard to market 
dynamics, the comment stated that FDA should consider the number of 
active suppliers and the percentage of the market supplied by such 
active suppliers. The comment stated that using this as a filter would 
help alert FDA to identify suppliers that are providing a significant 
percent of the market and that truly have the potential to create a 
drug shortage. For example, a market supplied by 10 active suppliers of 
equal market share would not likely experience a drug shortage if 1 of 
the active suppliers had a supply chain disruption. According to the 
comment, the market void could be absorbed by the nine other active 
suppliers via safety stock, additional production, etc. Therefore, the 
comment recommended the addition of a ``primary suppliers'' filter to 
separate those active suppliers who are supplying a significant percent 
to the market (i.e., such as 20 percent or more of the market).
    In addition, the comment stated that the duration of a supply chain 
shortage should be taken into consideration and utilized as a filter 
regarding drug shortage reporting. This filter would consider the 
typical inventory levels carried in the retail and wholesale channels. 
For example, an active supplier may have a supply disruption (i.e., 
product out of stock) for 30 days; however, the market may not 
experience

[[Page 38930]]

a drug shortage given the inventory levels in the retail and wholesale 
channels. Typical inventory levels within these channels could range 
from 30 to 60 days of supply; therefore, the comment proposed a 60-day 
potential supply disruption as the minimum duration for drug shortage 
reporting to avoid chances of inventory hoarding and artificial 
increases in market demand that ultimately undermine the intent of 
FDASIA.
    (Response) FDA declines to adopt the ``filters'' proposed to reduce 
reporting under the rule. FDA does not agree that these proposed 
``filters'' are consistent with the language or intent of FDASIA. As 
explained in the preamble to the proposed rule (78 FR 65904 at 65912), 
``meaningful disruption'' means a disruption in the applicant's own 
supply. This interpretation avoids the problem of expecting an 
applicant to predict the market-wide impact of its own interruption in 
manufacturing, which can be difficult to assess and could lead to 
inconsistent interpretation and less accurate predictions.
    (Comment 29) Two comments addressed the stockpile of VFC vaccines 
maintained by CDC as part of its vaccine shortage notification program 
and noted the success of the program in mitigating or completely 
eliminating supply disruptions. One of the comments requested that FDA 
permit applicants to take into consideration the existence of a CDC 
stockpile in assessing whether an interruption in manufacturing is 
reasonably likely to disrupt supply chains.
    (Response) We acknowledge the importance of the stockpile of VFC 
vaccines maintained by CDC. CDC and HHS are required to maintain a 
stockpile of routinely recommended vaccines for the United States in 
the event of vaccine shortages or other unanticipated supply problems. 
The national pediatric vaccines stockpile currently maintains 14 
pediatric vaccines that protect infants, children, and adolescents from 
15 vaccine-preventable diseases excluding influenza.\13\ Where 
appropriate, FDA and the manufacturers work together with CDC and take 
into consideration the existence of a CDC stockpile in assessing the 
impact of supply disruptions and the likelihood of a shortage. However, 
for the purposes of reporting under this rule, we do not agree that 
applicants should be permitted to take into consideration the existence 
of the CDC stockpile. As explained in section III.C.1.b.i, consistent 
with the statutory definition of meaningful disruption, the rule 
requires an applicant to report an interruption in manufacturing that 
is likely to lead to a meaningful disruption in its own supply of a 
covered drug or biological product. The rule does not require an 
applicant to predict the market-wide impact of an interruption in its 
own manufacturing, which can be difficult to accurately assess and 
could lead to inconsistent interpretation of the regulation, less 
accurate predictions, and under- or overreporting.
---------------------------------------------------------------------------

    \13\ See http://www.cdc.gov/phpr/documents/VacStockpileManual.pdf.
---------------------------------------------------------------------------

2. Timing and Submission of Notification
    (Comment 30) Three comments requested clarification of when the 
notification ``clock'' would start, in other words, exactly when the 
notification requirement would be triggered. Two of the comments 
explained that at the outset, a meaningful disruption might not appear 
``likely'' but may become ``likely'' as the events progress. The 
comments expressed concern that the Agency and the applicant may 
disagree about which event would trigger the notification requirement 
if it was not obvious to the applicant initially that a meaningful 
disruption would be likely. The comments suggested that the appropriate 
trigger to start the notification ``clock'' is the date on which 
information becomes available to the applicant from which it could be 
reasonably determined that a meaningful disruption is likely to occur. 
Another comment noted that the notification clock could begin on the 
date of the event causing the interruption, or on the date the 
applicant becomes aware that an interruption could cause a shortage. 
The comment cautioned that if the latter were considered the trigger, 
it may be difficult to determine the exact point in time.
    (Response) FDA expects that an applicant will notify FDA as soon as 
information becomes available to the applicant from which the applicant 
could reasonably determine that a meaningful disruption is likely to 
occur. As explained in section III.C.2.a of this document and the 
preamble to the proposed rule (78 FR 65904 at 65914), the applicant 
should not wait until the interruption in manufacturing actually begins 
to disrupt supply and affect patient access to the product. Early 
notification is the Agency's best tool for addressing shortages because 
it provides FDA with lead time to work with stakeholders to prevent the 
shortage or mitigate the impact of an unavoidable shortage. 
Accordingly, while not required, we encourage applicants to communicate 
with FDA even in situations where a meaningful disruption may appear to 
be possible though not necessarily likely.
    We understand the commenters' concern that FDA and the applicant 
may disagree about which event would trigger the notification 
requirement. FDA has sent and intends to continue sending noncompliance 
letters when the Agency believes an applicant failed to notify FDA as 
soon as practicable or within 5 business days of the discontinuance or 
interruption.\14\ If an applicant receives a noncompliance letter but 
believes the failure to notify was reasonable, the applicant should 
provide a full explanation of the circumstances in the applicant's 
response to the noncompliance letter. Consistent with section 
506C(f)(3) of the FD&C Act, FDA will carefully consider the explanation 
provided in determining whether there was a reasonable basis for not 
notifying the Agency. If FDA determines that there was a reasonable 
basis for not notifying the Agency in accordance with section 506C of 
the FD&C Act and this rule, we will not post the noncompliance letter 
or the applicant's response to FDA's Web site.
---------------------------------------------------------------------------

    \14\ As noted in section III.C.2.a, even if an applicant 
notifies FDA within 5 business days of the discontinuance or 
interruption, the applicant may be issued a noncompliance letter if 
FDA believes the applicant did not notify the Agency as soon as 
practicable.
---------------------------------------------------------------------------

    (Comment 31) Several comments addressed the proposal that if 6 
months' advance notice is not possible, notification must be submitted 
as soon as practicable thereafter, but in no case later than 5 business 
days after the permanent discontinuance or interruption in 
manufacturing occurs. Some comments expressed concern that FDA would 
allow an applicant to report as late as 5 days after a permanent 
discontinuance or interruption in manufacturing occurs. One comment 
stated that this would significantly weaken the rule and limit its 
effectiveness. The comment further stated that for an unforeseen 
disruption or discontinuation, FDA should require immediate 
notification or should outline what situations could arise that would 
appropriately necessitate a 5-day reporting delay. One comment 
expressed the view that reporting 5 days after the interruption should 
only be considered acceptable in rare circumstances, such as natural 
disaster. Another comment stated that applicants should be required to 
notify FDA a minimum of 6 months prior to the discontinuance or 
interruption, the only

[[Page 38931]]

exception being a natural disaster or catastrophic incident. The 
comment stated that the proposed language is vague and lenient and 
creates a loophole in mandatory reporting that ultimately serves 
neither the public health nor that of patients, while shielding 
manufacturers from their own failure to plan adequately.
    In contrast, some comments expressed concern that requiring 
notification no later than 5 business days after the discontinuance or 
interruption would not provide sufficient time for applicants to 
investigate and get a complete understanding of the issue. The comments 
explained that more than 5 business days may be necessary to confirm 
whether actions taken in response to the interruption will affect the 
manufacturer's ability to fill orders or meet expected demand. One 
comment stated that requiring notification before a full investigation 
has been completed is likely to lead to overreporting and less reliable 
information being provided to FDA. The comment stated that the ``as 
soon as practicable'' standard set forth in FDASIA provides the 
necessary flexibility and should not be altered by adding a 5 business 
day limit. One comment recommended that, if FDA believes a definite 
reporting timeframe is necessary, it should be no shorter than 15 days 
after the permanent discontinuance or interruption in manufacturing. 
Another comment proposed that if a timeframe is necessary, it could be 
extended to 15 days along with qualifying language, such as ``once it 
can conclusively be determined that a manufacturing issue will 
adversely impact supply.''
    (Response) FDA's most powerful tool for addressing drug and 
biological product shortages is early notification, which provides lead 
time for the Agency to work with manufacturers and other stakeholders 
to prevent a shortage or to mitigate the impact of unavoidable 
shortages. Accordingly, we expect that applicants will provide 6 
months' advance notice whenever possible. FDA understands, though, that 
an applicant may not reasonably be able to anticipate certain 
interruptions in manufacturing that are likely to lead to a meaningful 
disruption in supply 6 months in advance. In those situations, FDA 
requires notification ``as soon as practicable,'' but in no case more 
than 5 business days after the interruption in manufacturing occurs. 
The Agency has determined that 5 business days is adequate time for an 
applicant to assess whether the discontinuance or interruption in 
manufacturing is likely to lead to a meaningful disruption. As the 
situation evolves, FDA expects that applicants will provide the Agency 
with appropriate updates that will facilitate FDA's efforts. We believe 
that this timeframe appropriately balances the need for early 
notification and the understanding that applicants may not be able to 
immediately assess the impact of an interruption in manufacturing.
    If notification was required only when an applicant has confirmed 
that a meaningful disruption will occur, then it might be appropriate 
to provide additional time for applicants to make this determination. 
However, the statute requires notification when a discontinuance or 
interruption in manufacturing is likely to lead to a meaningful 
disruption. The statute takes account of the fact that there may be a 
degree of uncertainty about the outcome of the discontinuance or 
interruption. As such, we note that the qualifying language proposed by 
one comment (i.e., adding ``once it can conclusively be determined that 
a manufacturing issue will adversely impact supply'' to the 
notification requirement) would not be consistent with the statutory 
requirement to notify FDA when a discontinuance or interruption is 
likely to lead to a meaningful disruption. FDA believes it is 
reasonable for an applicant to make a determination about whether an 
interruption is likely to lead to a meaningful disruption in supply 
within 5 business days of the discontinuance or interruption. The 
Agency does not believe that 15 business days should be necessary to 
make such a determination, and a delay of 15 business days in 
notification could have a significant impact on FDA's ability to 
prevent or mitigate a shortage.
    We note that if an applicant receives a noncompliance letter for 
failure to notify the Agency within 5 business days of a discontinuance 
or interruption in manufacturing and believes that it would not have 
been reasonable to expect the applicant to determine that the event was 
likely to lead to a meaningful disruption, such information should be 
provided in the applicant's response to the noncompliance letter. The 
Agency, in turn, will consider that information in determining whether 
the applicant had a reasonable basis for not notifying FDA within the 
required timeframe and therefore whether the noncompliance letter 
should not be made public.
    (Comment 32) One comment suggested that the rule should 
specifically include ``natural disaster'' as a potential trigger for 
notification. The comment acknowledged that the preamble to the 
proposed rule notes that reportable interruptions in manufacturing may 
include natural disasters, but the commenter was concerned that the 
examples provided in the proposed rule were all circumstances under the 
control of the manufacturer.
    (Response) A wide variety of situations may lead to a reportable 
interruption in manufacturing (including natural disasters, equipment 
failure, or a delay in acquiring APIs or inactive ingredients), and FDA 
does not believe it is necessary or appropriate to include specific 
examples within the regulation itself. The Agency believes that the 
information and examples provided in the preamble to the proposed rule 
are adequate to assist applicants in determining whether a given 
interruption in manufacturing must be reported to FDA.
    (Comment 33) One comment recommended that FDA require manufacturers 
to provide periodic updates on actions they are taking to bring drugs 
that are in shortage back to the market. The comment stated that this 
would help FDA understand the reasons for any continued delays in 
delivering drugs into the supply chain and allow the Agency to work 
with manufacturers in a more informed manner to reduce shortages.
    (Response) Once FDA is notified of a situation that might lead to a 
shortage, FDA is in frequent contact with the applicant to seek ways to 
prevent the shortage. At this time, we do not believe that requiring 
periodic updates would be necessary, because we do not anticipate that 
requiring such updates would provide information that the Agency does 
not already have.
    (Comment 34) Two comments provided suggestions about the electronic 
submission of 506C notifications to FDA. One of the comments suggested 
that the rule should include the specific office within FDA that 
notifications should be sent to. The other comment noted that 
applicants currently submit information in a nonspecified format via 
email and stated that FDA should provide greater clarity on whether 
this practice is intended to continue once the rule goes into effect 
and whether FDA will be specifying a uniform process for applicants to 
follow when submitting notifications.
    (Response) As explained in the preamble to the proposed rule (78 FR 
65904 at 65915), applicants must email notifications to 
drugshortages@fda.hhs.gov (for products regulated by CDER) and 
cbershortages@fda.hhs.gov (for products regulated by CBER). In the 
future, the Agency may consider creating an electronic notification 
portal

[[Page 38932]]

to facilitate submission of these notifications. At that time, the 
Agency would provide any instructions necessary to use the portal. 
Because we expect that such a portal would be available on FDA's Web 
site, we do not believe it is necessary or appropriate to include the 
name of a specific receiving office in the regulation itself.
3. Contents of the Notification
    (Comment 35) Two comments recommended that information about 
mitigation be required in the notification. One of the comments 
suggested that FDA require the notification to include a description of 
the efforts by the applicant to prevent or mitigate the shortage. The 
other comment recommended that FDA require the notification to include 
a mitigation strategy or, at least, suggestions for mitigation.
    (Response) FDA agrees that input from the applicant about ways to 
prevent or mitigate the shortage is crucial. The Agency, however, does 
not agree that it is appropriate to require information about 
mitigation to be included in the notification. We are concerned that 
there could be a delay in the notification if applicants are required 
to develop a mitigation strategy to include in the notification while 
also working to resolve the underlying issue. Instead, we have 
determined that it is appropriate to require basic information that is 
necessary for the Agency to take action and that the Agency is required 
to include in the shortages list under section 506E of the FD&C Act. We 
strongly encourage applicants to provide additional information, 
including proposals to prevent or mitigate the shortage, inventory on 
hand or in distribution channels, allocation procedures and/or plans 
for releasing available product, market share, or other information 
that may assist FDA.
    (Comment 36) One comment suggested that FDA require the 
notification to indicate whether the drug or biological product is 
being used in an FDA- or National Cancer Institute-approved clinical 
trial. The comment explained that many clinical trials, especially for 
cancer treatments, are designed to test the safety and efficacy of the 
standard of care against, or in combination with, a new treatment being 
investigated. Accordingly, drug shortages have an impact on clinical 
trials, not just on patients undergoing standard treatment.
    (Response) FDA understands that drug and biological product 
shortages may have an impact on clinical trials in addition to patients 
receiving standard treatment. However, we believe that requiring an 
applicant to state, in its notification, whether the product is 
currently being used in a clinical trial would require additional 
investigation by the applicant and would be unnecessarily burdensome. 
FDA updates the drug and biological product shortage lists regularly, 
and we encourage investigators to sign up for email updates or the RSS 
feed to make sure they are aware of the latest information regarding 
product shortages.
    (Comment 37) One comment requested clarification on what 
information must be included in a notification provided by the 
manufacturer of a covered drug marketed without an approved 
application.
    (Response) As required by Sec.  310.306, manufacturers of a covered 
drug marketed without an approved application must provide the same 
information in a notification as do applicants under Sec.  
314.81(b)(3)(iii)(c).
4. Public Lists of Products in Shortage
    (Comment 38) Two comments requested clarification about whether FDA 
will maintain a single list that includes shortages of both drugs and 
biological products.
    (Response) At the present time, FDA intends to maintain separate 
lists of CDER-regulated and CBER-regulated products that are in 
shortage. The lists are available on FDA's Web site at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (for products 
regulated by CDER) and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (for products regulated by 
CBER).
    (Comment 39) One comment expressed support for the proposed 
addition of ``other reason'' to the list of statutory reasons for the 
shortage that FDA could choose from. The comment noted that the seven 
reasons outlined in FDASIA may be difficult to apply in certain 
situations.
    (Response) FDA agrees that the categories provided in FDASIA do not 
necessarily cover certain quality or manufacturing problems that may 
result in a shortage. Therefore, the Agency is finalizing ``other 
reason'' as an additional category that the Agency may identify.
    (Comment 40) Three comments requested clarification of whether FDA 
would include potential drug and biological product shortages in the 
public lists, in addition to actual shortages. The comments expressed 
concern that disseminating information about potential shortages could 
result in unintended consequences, such as hoarding.
    (Response) Under section 506E of the FD&C Act, FDA maintains an up-
to-date list of drugs that are determined by FDA to be in shortage in 
the United States. Section 506C(h)(2) of the FD&C Act defines a 
shortage as ``a period of time when the demand or projected demand for 
the drug within the United States exceeds the supply of the drug.''
    (Comment 41) Two comments requested clarification on the process 
and criteria FDA uses to determine whether there is an actual shortage 
and the process and criteria FDA uses to determine whether to remove a 
product from the shortages list.
    (Response) The MAPP on shortages of CDER-regulated products (MAPP 
4190.1 Rev. 2, p. 14) and SOPP on shortages of CBER-regulated Products 
explain in detail the process and criteria FDA uses to verify if an 
actual shortage exists. The MAPP (p. 17) also explains the process and 
criteria FDA uses to determine whether a product should be removed from 
the shortages list.
    (Comment 42) Several comments noted that FDA is responsible for 
determining whether, in fact, an actual shortage exists as well as the 
categorical reason for the shortage that best fits the particular 
situation. The comments requested that FDA consult with applicants 
about these determinations before making the information public. One 
comment noted that this has been FDA's practice and requested that the 
Agency continue this collaborative approach. Another comment 
specifically requested that FDA develop a process by which the Agency 
shares its intended public communication prior to posting it on FDA's 
Web site to allow applicants the opportunity to make corrections, 
including those related to unintentional disclosure of confidential or 
proprietary information.
    (Response) FDA verifies all information with the applicants prior 
to posting information on FDA's Web site. Applicants also review the 
information posted on the Web site regularly and provide updates to FDA 
as new information becomes available.
    (Comment 43) One comment noted that the rule does not address how 
the estimated shortage durations are determined. The comment stated 
that the estimated duration of shortages of some common medications, 
such as injectable calcium and phosphate preparations, listed on FDA's 
Web site have been inaccurate, which has made it difficult to develop 
strategies to prioritize care for those patients most in need of these 
drugs. The comment also expressed concern that there are no

[[Page 38933]]

consequences for gross underestimations of durations of shortages. The 
comment recommended that FDA address these issues in the final rule.
    (Response) The estimated shortage duration that is provided on 
FDA's Web site is intended to capture the particular applicant's 
anticipated recovery time and is based on information provided by the 
applicant. FDA communicates with applicants on a daily basis and 
updates the Web site with estimated recovery time as information 
becomes available from the applicants. The Agency makes every effort to 
provide as much information as possible and works closely with 
applicants to ensure that the Web site lists the most current 
information.
    (Comment 44) One comment expressed concern about including each 
presentation of a drug product (e.g., strength, dosage form, route of 
administration) that is determined to be in shortage in the public 
shortage list when alternate presentations of the same product remain 
available. The comment stated that section 503B of the FD&C Act (21 
U.S.C. 353b) permits a compounder to begin manufacturing a drug once it 
is on the section 506E shortage list. As such, the comment stated that 
compounders may begin manufacturing a product on the list, even if 
there are other available presentations that would be adequate 
substitutes. The comment stated that compounded products raise grave 
public health concerns and urged FDA to provide examples of situations 
in which the Agency will not list a drug or biological product because 
a suitable substitute is available. The comment stated that such a 
clarification would be consistent with the public health exception to 
the statutory requirement for FDA to publicly disclose, to the maximum 
extent possible, information on drug shortages.
    (Response) The Agency does not agree that withholding particular 
presentations of a drug from the shortage list because other 
presentations are available would be appropriate or beneficial to the 
public health. Other comments received on the proposed rule, and our 
own experience, indicate the importance to health care professionals of 
being made aware of shortages of any presentation of a given drug 
product to ensure that they have the most accurate information about 
products in shortage and can make treatment decisions accordingly. We 
do not think the potential risk identified by the comment outweighs the 
benefit to health care providers and patients of having this 
information. We note further that while section 503B of the FD&C Act 
does permit compounding of drug products listed in the drug shortages 
list, only the specific presentations included in the drug shortages 
list may be compounded. Moreover, facilities that compound under 
section 503B must comply with the current good manufacturing practice 
requirements under section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 
351(a)(2)(B)).
    (Comment 45) One comment suggested that FDA communicate directly 
with physician organizations and affected specialty societies about 
shortages so that the impact of the shortage can be minimized.
    (Response) FDA agrees that communication about products that are in 
shortage is essential to ensure that health care providers have the 
information they need to make appropriate treatment decisions. We note 
that in FDA's drug and biological products shortages Web pages, 
individuals may sign up to receive email updates of shortage 
information. Drug and biological product shortage updates are also 
available by RSS feed.
    (Comment 46) One comment recommended that FDA establish a mechanism 
whereby physicians can receive shortage information about specific 
therapeutic categories via email updates, an RSS feed, or through a 
smartphone application. The comment stated that these targeted 
communications would allow physicians to receive only the information 
they need.
    (Response) Physicians and other interested stakeholders can receive 
information about specific therapeutic categories or specific products 
via email updates and RSS feed by signing up on FDA's Web site. In 
addition, in March 2015, FDA launched a mobile application (app) 
designed to facilitate access to information about drug shortages. The 
app identifies current drug shortages, resolved shortages, and 
discontinuances of drug products. The app allows users to search by a 
drug's generic name or active ingredient and also by therapeutic 
category. The app is available for free download via iTunes (for Apple 
devices) and the Google Play store (for Android devices) by searching 
``FDA Drug Shortages.''
    (Comment 47) One comment stated that it would be helpful if the 
information contained in FDA's Drug Shortage Web site were categorized 
by specific classes of drugs in shortage that are relative to a 
particular area of research, such as oncology. The comment stated that 
by categorizing the information in this way, FDA could quickly notify 
researchers of drug shortages in classes frequently used by researchers 
in a particular specialty.
    (Response) FDA's Drug Shortage Web site, which was redesigned after 
publication of the proposed rule, currently lists products 
alphabetically as well as by therapeutic category. This enables health 
care providers and other interested parties to access information 
relevant to particular specialties more easily.
    (Comment 48) One comment recommended that FDA include information 
on the shortages Web sites indicating whether the drug or biological 
products listed are being utilized in an FDA-approved clinical trial. 
The comment also stated a link should be provided to the 
clinicaltrials.gov Web site for each clinical trial in which the 
product is being used.
    (Response) FDA shares the commenter's concern about the impact that 
drug and biological product shortages may have on clinical trials that 
test investigational products against the standard of care. However, 
the shortages Web sites as well as clinicaltrials.gov are updated 
regularly, and it would not be feasible, at this time, to maintain 
links between the products on the shortages lists and the separate Web 
site that lists clinical trials in which the products may be used. FDA 
encourages investigators and sponsors to sign up for email updates or 
RSS feed and to visit FDA's Web site for the most up-to-date 
information about drug and biological product shortages. We also 
encourage sponsors to discuss with the appropriate review division any 
contingency plans if there is a shortage of products being used in a 
clinical trial.
5. Confidentiality and Disclosure
    (Comment 49) Two comments noted the provision in the proposed rule 
that ``FDA may choose not to make information . . . available on the 
drug shortages list . . . if FDA determines that disclosure of such 
information would adversely affect the public health (such as by 
increasing the possibility of hoarding or other disruption of the 
availability of the drug to patients).'' The comments stated that the 
provision presumes that FDA is uniquely qualified to determine the 
relative value and/or risk associated with public dissemination of 
information related to product supply and product shortages. The 
comments suggest that, at a minimum, FDA should incorporate applicants' 
input into the decisionmaking regarding public dissemination of 
information related to supply constraints.

[[Page 38934]]

    (Response) The provision of the proposed rule referenced in the 
comment codifies section 506E(c)(3), which reflects Congress' intent 
that FDA should have the discretion not to make information public if 
the Agency determines that disclosure would adversely affect public 
health. We welcome stakeholder input on all shortage-related matters. 
However, consistent with the statute, it is ultimately FDA's 
determination whether disclosure of information would adversely affect 
public health.
6. Failure To Notify
    (Comment 50) Three comments requested that FDA establish a process 
for issuing and adjudicating noncompliance letters sent to an applicant 
for failure to notify FDA as required by section 506C(a) of the FD&C 
Act. The comments expressed concern about potential disagreements 
between the Agency and the applicant about what constitutes timely 
notification and stressed the importance of a dialogue between FDA and 
the applicant before a noncompliance letter is issued. One comment 
specifically requested a process by which an applicant may appeal a 
decision to issue a noncompliance letter and confirmation from FDA that 
it will retract and remove any noncompliance letter from the Web site 
if the appeal is successful.
    (Response) FDA believes that the process set forth in section 
506C(f) of the FD&C Act (and codified in the final rule) is 
sufficiently clear. The Agency will send a noncompliance letter to an 
applicant for failure to notify FDA, which includes failure to timely 
notify FDA, of a permanent discontinuance or interruption in 
manufacture that is likely to lead to a meaningful disruption in the 
supply of a drug in the United States. As provided in the statute, not 
later than 30 calendar days following issuance, the applicant must 
submit a response to the noncompliance letter. If an applicant believes 
it received a noncompliance letter in error, the applicant should 
provide in its response a full explanation, including relevant dates 
surrounding the event in question, and any other information of which 
FDA should be made aware. The Agency, in turn, will consider the 
information provided in determining whether the noncompliance letter 
was issued in error or there was a reasonable basis for not notifying 
the Agency. If FDA determines that the original letter was issued in 
error or that the recipient had a reasonable basis for not notifying 
FDA, then the Agency will not post the noncompliance letter or response 
to the Web site. In light of the process and timeframes specified in 
section 506C(f) of the FD&C Act, FDA does not believe that a separate 
appeals process or any further clarification is necessary at this time.
    (Comment 51) Two comments requested that FDA establish a process to 
ensure that no confidential or proprietary information is released when 
a noncompliance letter and the applicant's response is posted to FDA's 
Web site.
    (Response) As required by section 506C(f)(3) of the FD&C Act, 
appropriate redactions will be made before a noncompliance letter and 
the applicant's response are posted to FDA's Web site. FDA has 
extensive experience redacting confidential and proprietary 
information, e.g., from NDA and BLA approval packages, before posting 
documents to the Web site. We believe that the systems the Agency has 
in place are adequate to address the redaction of noncompliance letters 
and any response submitted by the applicant.
    (Comment 52) One comment requested confirmation that FDA intends to 
address the failure to notify through the noncompliance letter process 
and not by GMP inspections.
    (Response) If an applicant fails to notify FDA as specified in the 
final rule, the Agency will address such failure through the process 
outlined in section 506C(f) of the FD&C Act and codified in this rule.
    (Comment 53) One comment suggested that FDA should provide notice 
of noncompliance to the major news services as well as posting the 
information on FDA's Web site. The comment stated that in this way, 
consumers, distributors, and other stakeholders will have knowledge of 
which companies have not complied with the notification requirement.
    (Response) Consistent with section 506C(f) of the FD&C Act, FDA 
intends to make noncompliance letters and any response to such letters 
public by posting them on FDA's Web site, unless FDA determines that 
the noncompliance letter was issued in error or, after reviewing the 
applicant's response, determines that the applicant had a reasonable 
basis for not notifying.
    (Comment 54) One comment stated that FDA should be better empowered 
to enforce the notification requirement, potentially by being given 
authority to fine companies that are noncompliant.
    (Response) As explained in the comment to the previous response, 
FDA will address noncompliance in the manner prescribed in section 
506C(f) of the FD&C Act.

D. Other Issues Raised

    (Comment 55) Multiple comments requested that FDA work with other 
Agencies and professional societies to develop treatment guidelines 
when drug and biological products are in shortage.
    (Response) FDA does not typically develop treatment guidelines. We 
note that some professional societies, such as the American Society of 
Health-System Pharmacists, do provide treatment guidelines that 
interested parties may consult.
    (Comment 56) Several comments stated that notification only of a 
permanent discontinuance or an interruption in manufacturing is not 
sufficient to address the drug shortage problem. The comments noted 
that steps need to be taken to address manufacturing problems that may 
lead to product shortages. The comments also suggested that, in 
addition to notification, there should be a plan in place to either 
import an equivalent drug from other countries or assign a firm to 
manufacture the drug.
    (Response) FDA appreciates and shares the commenters' concern about 
the problem of drug and biological product shortages. However, these 
comments are beyond the scope of this rulemaking. The Agency is issuing 
the final rule to implement sections 506C and 506E of the FD&C Act, 
which require notification of a permanent discontinuance or an 
interruption in manufacturing of certain covered products and 
maintenance by FDA of a publicly available list of drugs that are 
determined by FDA to be in shortage. As explained in section I, 
consistent with FDA's authority under the FD&C Act, the Agency uses a 
variety of tools to prevent or mitigate drug and biological product 
shortages, and early notification is crucial to FDA's efforts. However, 
FDA does not have authority over an applicant's business decisions 
regarding the manufacture of particular products.
    (Comment 57) One comment raised issues concerning the preliminary 
regulatory impact analysis and the Agency's assessment of the net 
benefit of the rulemaking.
    (Response) Our response is provided in the full discussion of 
economic impacts available in Docket No. FDA-2011-N-0898 (Ref. 4) and 
at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

V. Legal Authority

    FDA is amending its regulations to implement sections 506C and 506E 
of the FD&C Act as amended by FDASIA. FDA's authority for this rule 
also

[[Page 38935]]

derives from section 701(a) of the FD&C Act (21 U.S.C. 371(a)).

VI. Economic Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The Agency believes that this final rule is an economically 
significant regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The estimated per notification cost for small 
business entities, $227, represents a small percentage of average 
annual sales (up to 0.10 percent). Although the final rule does not 
require specific mitigation strategies, for firms that choose to 
implement mitigation or prevention strategies, it is possible that 
additional costs of $113,000 associated with implementing mitigation 
strategies could be significant: 2 to 7.8 percent of average annual 
sales for companies with fewer than 20 employees. In FDA's experience 4 
to 5 small businesses entities per year have been affected by a 
shortage. The Agency certifies that the final rule will not have a 
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $144 million, using the most current (2014) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

B. Summary

    The final rule amends FDA's regulations to implement sections 506C 
and 506E of the FD&C Act, as amended by FDASIA. The final rule requires 
all applicants of covered, approved prescription drug or biological 
products other than blood or blood components for transfusion (referred 
to as blood or blood components), all applicants of blood or blood 
components that manufacture a significant percentage of the U.S. blood 
supply, and all manufacturers of covered prescription drugs marketed 
without an approved application, to notify FDA electronically of a 
permanent discontinuance or an interruption in manufacturing of the 
product that is likely to lead to a meaningful disruption in supply (or 
a significant disruption in supply for blood or blood components) of 
the product in the United States 6 months in advance of the permanent 
discontinuance or interruption in manufacturing, or, if that is not 
possible, as soon as practicable, but no later than 5 business days 
after the permanent discontinuance or interruption occurs. The final 
rule also describes how to submit such a notification, the information 
required to be included in such a notification, the consequences for 
failure to submit a required notification, the disclosure of shortage-
related information, and the meaning of certain terms.
    The final rule would impose annual costs of up to $40.54 million on 
those applicants or entities affected by the rule, and up to $6.38 
million on FDA in preventive costs. Estimated total annual costs of the 
interactions between industry and FDA range between $14.54 million and 
$46.92 million. Discounting over 20 years, annual quantified benefits 
from avoiding the purchase of more expensive alternative products, 
managing product shortages, and life-years gained, would range from 
$30.45 million to $98.65 million using a 3 percent discount rate, and 
from $30.39 million to $98.42 million using a 7 percent discount rate. 
Annualized over 20 years, net benefits range between $15.90 million and 
$51.72 million using a 3 percent discount rate; they range between 
$15.85 million and $51.50 million using a 7 percent discount rate. The 
public health benefits, mostly non-quantified, include the value of 
information that would assist FDA, manufacturers, health care 
providers, and patients in evaluating, mitigating, and preventing 
shortages of drug and biological products that could otherwise result 
in non-fatal adverse events, errors, delayed patient treatment, or 
interruption in clinical trial development. The costs and benefits are 
summarized in table 1.
    Under the current environment all notifications provide meaningful 
information to identify a shortage or to prevent one, but there is 
uncertainty whether the scope of the rule could result in notifications 
that do not provide information about any shortage and lead to 
additional costs.
    The full discussion of economic impacts is available in Docket No. 
FDA-2011-N-0898 and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 4).

                                      Table 1--Summary of Benefits, Costs and Distributional Effects of Final Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                 Discount
                   Category                       Primary       Low        High        Year        rate       Period                  Notes
                                                 estimate    estimate    estimate     dollars    (percent)    covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/year)........     $64.545     $30.445     $98.645        2013           3     2015-34  There is uncertainty surrounding
                                                   $64.408     $30.390     $98.425        2013           7     2015-34   these estimates because some
                                                                                                                         underlying estimates came from
                                                                                                                         non-representative studies.
Annualized Quantified.........................  ..........  ..........  ..........  ..........           3     2015-34  17-55 preventable shortages per
                                                                                                         7     2015-34   year.

[[Page 38936]]

 
Qualitative...................................  Reduction in errors and non-fatal adverse events associated with shortages; uninterrupted patient access
                                                  to drugs and biological products necessary for treatment; continued access to drugs used in clinical
                                                                                           trial development.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                          Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/year)........     $30.731     $14.540     $46.921        2013           3     2015-34  There is uncertainty about
                                                   $30.731     $14.540     $46.921        2013           7     2015-34   potential noise from
                                                                                                                         notifications that might not
                                                                                                                         provide meaningful information,
                                                                                                                         but which could result in
                                                                                                                         additional review costs. In
                                                                                                                         addition, these estimates
                                                                                                                         assume that applicants will
                                                                                                                         participate in mitigation or
                                                                                                                         preventive strategies.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Quantified.........................                                               None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative...................................                                               None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized (millions $/year)                                               None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized Monetized (millions $/year)..                                               None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                         Effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local or Tribal Gov't..................                                                    None.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Small Business................................    Based on the analysis small business entities covered by the final rule could incur small costs, $227
                                                 per notification or up to 0.10 percent of their average annual sales. Although the final rule would not
                                                  require it, some firms may choose to incur additional costs associated with mitigation or prevention
                                                                                               strategies.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Wages.........................................                                            No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Growth........................................                                            No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the 
information collection provisions are shown in the following paragraphs 
with an estimate of the total reporting burden. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    Title: Permanent Discontinuance or Interruption in Manufacturing of 
Certain Drug or Biological Products; Final Rule
    Description: Under the final rule, applicants with an approved NDA 
or ANDA for a covered drug product, manufacturers of a covered drug 
product marketed without an approved application, and applicants with 
an approved BLA for a covered biological product (including certain 
applications of blood or blood components) must notify FDA in writing 
of a permanent discontinuance of the manufacture of the drug or 
biological product or an interruption in manufacturing of the drug or 
biological product that is likely to lead to a meaningful disruption in 
the applicant's supply (or a significant disruption for blood or blood 
components) of that product. The notification is required if the drug 
or biological product is life supporting, life sustaining, or intended 
for use in the prevention or treatment of a debilitating disease or 
condition, including use in emergency medical care or during surgery, 
and if the drug or biological product is not a radiopharmaceutical drug 
product.
    The final rule requires that the notification include the following 
information: (1) The name of the drug or biological product subject to 
the notification, including the NDC (or, for a biological product that 
does not have an NDC, an alternative standard for identification and 
labeling that has been recognized as acceptable by the Center 
Director); (2) the name of each applicant of the drug or biological 
product; (3) whether the notification relates to a permanent 
discontinuance of the drug or biological product or an interruption in 
manufacturing of the product; (4) a description of the reason for the 
permanent discontinuance or interruption in manufacturing; and (5) the 
estimated duration of the interruption in manufacturing.
    Under the final rule, the notification must be submitted to FDA 
electronically at least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing. If 6 months' advance 
notice is not possible because the permanent discontinuance or 
interruption in manufacturing was

[[Page 38937]]

unanticipated 6 months in advance, the applicant must notify FDA as 
soon as practicable, but in no case later than 5 business days after 
the permanent discontinuance or interruption in manufacturing occurs.
    If an applicant fails to submit the required notification, FDA will 
issue a letter informing the applicant or manufacturer of its 
noncompliance. The applicant must submit to FDA, not later than 30 
calendar days after FDA issues the letter, a written response setting 
forth the basis for noncompliance and providing the required 
notification.
    Description of Respondents: Applicants of prescription drugs and 
biological products subject to an approved NDA, ANDA, or BLA, and 
manufacturers of prescription drug products marketed without an 
approved ANDA or NDA, if the product is life supporting, life 
sustaining, or intended for use in the prevention or treatment of a 
debilitating disease or condition, including use in emergency medical 
care or during surgery, and is not a radiopharmaceutical product. If 
the BLA applicant is a manufacturer of blood or blood components, it is 
only subject to this rule if it manufactures a significant percentage 
of the nation's blood supply.
    Burden Estimates: Based on the number of drug and biological 
product shortage related notifications we have seen during the past 12 
months, we estimate that annually a total of approximately 75 
respondents (``Number of Respondents'' in table 2) will notify us of a 
permanent discontinuance of the manufacture of a drug or biological 
product or an interruption in manufacturing of a drug or biological 
product that is likely to lead to a meaningful disruption in the 
respondent's supply of that product under the final rule. We estimate 
that these respondents will submit annually a total of approximately 
305 notifications as required under Sec. Sec.  310.306, 
314.81(b)(3)(iii), and 600.82. Approximately 80 of these notifications 
are notifications that we currently receive under OMB control number 
0910-0699 for the IFR, thus we expect to receive approximately 225 new 
notifications under the final rule (``Total Annual Responses'' in table 
2).\15\ We estimate three notifications per respondent, because a 
respondent may experience multiple discontinuances or interruptions in 
manufacturing in a year that require notification (``No. of Responses 
per Respondent'' in table 2). We also estimate that preparing and 
submitting these notifications to FDA will take approximately 2 hours 
per respondent (``Hours per Response'' in table 2).
---------------------------------------------------------------------------

    \15\ This estimate is based on the number of new notifications 
we anticipate receiving under the final rule as compared to 
notifications we currently receive under the IFR. The IFR is our 
baseline for comparison for purposes of estimating the burden under 
the PRA, because additional notifications that we may currently 
receive, but that are not required under the IFR are not covered 
under any existing OMB control number, and thus must be captured in 
this PRA estimate. In contrast, the analysis of impacts of the final 
rule estimates the costs and benefits as compared to current 
practice. As a result of the use of different baselines for 
comparison, the estimate of new notifications under the PRA does not 
match the estimate of new notifications included in the final 
analysis of impacts.
---------------------------------------------------------------------------

    We base these estimates on our experience with the reporting of 
similar information to FDA since the issuance of the President's 
Executive Order 13588 of October 31, 2011 (Ref. 1), and under the 
interim final rule entitled ``Applications for Food and Drug 
Administration Approval To Market a New Drug; Revision of Postmarketing 
Reporting Requirements--Permanent'' (76 FR 78530; December 19, 2011).
    FDA estimates the burden of this collection of information as 
follows:

                                                         Table 2--Estimated Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                           21 CFR Section                               Number of      responses per     Total annual      Hours per       Total hours
                                                                       respondents       respondent       responses         response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notifications required under Sec.  Sec.   310.306 (unapproved                    75                3              225                2              450
 drugs), 314.81(b)(3)(iii) (products approved under an NDA or
 ANDA), and 600.82 (products approved under a BLA).................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.

    The information collection provisions of this final rule have been 
submitted to OMB for review, as required by section 3507(d) of the PRA. 
Prior to the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

VIII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the Agency concludes that 
the rule does not contain policies that have federalism implications as 
defined in the Executive order and, consequently, a federalism summary 
impact statement is not required.

IX. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

X. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified all the Web site addresses in this reference section, but 
we are not responsible for any subsequent changes to the Web sites 
after this document publishes in the Federal Register.)

    1. Executive Order 13588, ``Reducing Prescription Drug 
Shortages,'' October 31, 2011, available at http://www.gpo.gov/fdsys/pkg/FR-2011-11-03/pdf/2011-28728.pdf, accessed May 2015.

[[Page 38938]]

    2. Center for Drug Evaluation and Research, Manual of Policies 
and Procedures 4190.1 Rev. 2, ``Drug Shortage Management,'' 
September 3, 2014, available at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm079936.pdf, accessed May 2015.
    3. Center for Biologics Evaluation and Research, Standard 
Operating Policy and Procedure 8506, ``Management of Shortages of 
CBER-Regulated Products,'' April 9, 2012, available at http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/proceduressopps/ucm299304.htm, accessed May 2015.
    4. ``Regulatory Impact Analysis, Regulatory Flexibility 
Analysis, and Unfunded Mandates Reform Act Analysis for Permanent 
Discontinuance or Interruption in Manufacturing of Certain Drug or 
Biological Products''; Final Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR parts 20, 310, 314, and 600 are 
amended as follows:

PART 20--PUBLIC INFORMATION

0
1. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21 
U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.


0
2. Revise Sec.  20.100 by adding paragraph (c)(45) to read as follows:


Sec.  20.100  Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (45) Postmarket notifications of a permanent discontinuance or an 
interruption in manufacturing of certain drugs or biological products, 
in Sec. Sec.  310.306, 314.81(b)(3)(iii), and 600.82 of this chapter.

PART 310--NEW DRUGS

0
3. The authority citation for 21 CFR part 310 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356c, 356e, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 216, 
241, 242(a), 262, 263b-263n.


0
4. Add Sec.  310.306 to subpart D to read as follows:


Sec.  310.306  Notification of a permanent discontinuance or an 
interruption in manufacturing of marketed prescription drugs for human 
use without approved new drug applications.

    (a) Applicability. Marketed prescription drug products that are not 
the subject of an approved new drug or abbreviated new drug application 
are subject to this section.
    (b) Notification of a permanent discontinuance or an interruption 
in manufacturing. The manufacturer of each product subject to this 
section must make the notifications required under Sec.  
314.81(b)(3)(iii) of this chapter and otherwise comply with Sec.  
314.81(b)(3)(iii) of this chapter. If the manufacturer of a product 
subject to this section fails to provide notification as required under 
Sec.  314.81(b)(3)(iii), FDA will send a letter to the manufacturer and 
otherwise follow the procedures set forth under Sec.  
314.81(b)(3)(iii)(e).
    (c) Drug shortages list. FDA will include on the drug shortages 
list required by Sec.  314.81(b)(3)(iii)(d) drug products that are 
subject to this section that it determines to be in shortage. For such 
drug products, FDA will provide the names of each manufacturer rather 
than the names of each applicant. With respect to information collected 
under this paragraph, FDA will observe the confidentiality and 
disclosure provisions set forth in Sec.  314.81(b)(3)(iii)(d)(2).

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
5. The authority citation for 21 CFR part 314 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 
356b, 356c, 356e, 371, 374, 379e, 379k-1.


0
6. Revise Sec.  314.81(b)(3)(iii) to read as follows:


Sec.  314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (3) * * *
    (iii) Notification of a permanent discontinuance or an interruption 
in manufacturing. (a) An applicant of a prescription drug product must 
notify FDA in writing of a permanent discontinuance of manufacture of 
the drug product or an interruption in manufacturing of the drug 
product that is likely to lead to a meaningful disruption in supply of 
that drug in the United States if:
    (1) The drug product is life supporting, life sustaining, or 
intended for use in the prevention or treatment of a debilitating 
disease or condition, including any such drug used in emergency medical 
care or during surgery; and
    (2) The drug product is not a radiopharmaceutical drug product.
    (b) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must be submitted to FDA electronically in a format that FDA 
can process, review, and archive:
    (1) At least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing; or
    (2) If 6 months' advance notice is not possible because the 
permanent discontinuance or interruption in manufacturing was not 
reasonably anticipated 6 months in advance, as soon as practicable 
thereafter, but in no case later than 5 business days after the 
permanent discontinuance or interruption in manufacturing occurs.
    (c) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must include the following information:
    (1) The name of the drug subject to the notification, including the 
NDC for such drug;
    (2) The name of the applicant;
    (3) Whether the notification relates to a permanent discontinuance 
of the drug or an interruption in manufacturing of the drug;
    (4) A description of the reason for the permanent discontinuance or 
interruption in manufacturing; and
    (5) The estimated duration of the interruption in manufacturing.
    (d)(1) FDA will maintain a publicly available list of drugs that 
are determined by FDA to be in shortage. This drug shortages list will 
include the following information:
    (i) The names and NDC(s) for such drugs;
    (ii) The name of each applicant for such drugs;
    (iii) The reason for the shortage, as determined by FDA from the 
following categories: Requirements related to complying with good 
manufacturing practices; regulatory delay; shortage of

[[Page 38939]]

an active ingredient; shortage of an inactive ingredient component; 
discontinuation of the manufacture of the drug; delay in shipping of 
the drug; demand increase for the drug; or other reason; and
    (iv) The estimated duration of the shortage.
    (2) FDA may choose not to make information collected to implement 
this paragraph available on the drug shortages list or available under 
section 506C(c) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
356c(c)) if FDA determines that disclosure of such information would 
adversely affect the public health (such as by increasing the 
possibility of hoarding or other disruption of the availability of the 
drug to patients). FDA will also not provide information on the public 
drug shortages list or under section 506C(c) of the Federal Food, Drug, 
and Cosmetic Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 
552(b)(4), including trade secrets and commercial or financial 
information that is considered confidential or privileged under Sec.  
20.61 of this chapter.
    (e) If an applicant fails to submit a notification as required 
under paragraph (b)(3)(iii)(a) of this section and in accordance with 
paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to 
the applicant informing it of such failure.
    (1) Not later than 30 calendar days after the issuance of such a 
letter, the applicant must submit to FDA a written response setting 
forth the basis for noncompliance and providing the required 
notification under paragraph (b)(3)(iii)(a) of this section and 
including the information required under paragraph (b)(3)(iii)(c) of 
this section; and
    (2) Not later than 45 calendar days after the issuance of a letter 
under paragraph (b)(3)(iii)(e) of this section, FDA will make the 
letter and the applicant's response to the letter public, unless, after 
review of the applicant's response, FDA determines that the applicant 
had a reasonable basis for not notifying FDA as required under 
paragraph (b)(3)(iii)(a) of this section.
    (f) The following definitions of terms apply to paragraph 
(b)(3)(iii) of this section:
    Drug shortage or shortage means a period of time when the demand or 
projected demand for the drug within the United States exceeds the 
supply of the drug.
    Intended for use in the prevention or treatment of a debilitating 
disease or condition means a drug product intended for use in the 
prevention or treatment of a disease or condition associated with 
mortality or morbidity that has a substantial impact on day-to-day 
functioning.
    Life supporting or life sustaining means a drug product that is 
essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life.
    Meaningful disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of a drug by a 
manufacturer that is more than negligible and affects the ability of 
the manufacturer to fill orders or meet expected demand for its 
product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or insignificant changes in 
manufacturing so long as the manufacturer expects to resume operations 
in a short period of time.
* * * * *


Sec.  314.91  [Removed]

0
7. Remove Sec.  314.91.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
8. The authority citation for 21 CFR part 600 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360, 
360i, 371, 374, 379k-1; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-
25.


0
9. Add Sec.  600.82 to subpart D to read as follows:


Sec.  600.82  Notification of a permanent discontinuance or an 
interruption in manufacturing.

    (a) Notification of a permanent discontinuance or an interruption 
in manufacturing. (1) An applicant of a biological product, other than 
blood or blood components for transfusion, which is licensed under 
section 351 of the Public Health Service Act, and which may be 
dispensed only under prescription under section 503(b)(1) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), must notify 
FDA in writing of a permanent discontinuance of manufacture of the 
biological product or an interruption in manufacturing of the 
biological product that is likely to lead to a meaningful disruption in 
supply of that biological product in the United States if:
    (i) The biological product is life supporting, life sustaining, or 
intended for use in the prevention or treatment of a debilitating 
disease or condition, including any such biological product used in 
emergency medical care or during surgery; and
    (ii) The biological product is not a radiopharmaceutical biological 
product.
    (2) An applicant of blood or blood components for transfusion, 
which is licensed under section 351 of the Public Health Service Act, 
and which may be dispensed only under prescription under section 503(b) 
of the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing 
of a permanent discontinuance of manufacture of any product listed in 
its license or an interruption in manufacturing of any such product 
that is likely to lead to a significant disruption in supply of that 
product in the United States if:
    (i) The product is life supporting, life sustaining, or intended 
for use in the prevention or treatment of a debilitating disease or 
condition, including any such product used in emergency medical care or 
during surgery; and
    (ii) The applicant is a manufacturer of a significant percentage of 
the U.S. blood supply.
    (b) Submission and timing of notification. Notifications required 
by paragraph (a) of this section must be submitted to FDA 
electronically in a format that FDA can process, review, and archive:
    (1) At least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing; or
    (2) If 6 months' advance notice is not possible because the 
permanent discontinuance or interruption in manufacturing was not 
reasonably anticipated 6 months in advance, as soon as practicable 
thereafter, but in no case later than 5 business days after such a 
permanent discontinuance or interruption in manufacturing occurs.
    (c) Information included in notification. Notifications required by 
paragraph (a) of this section must include the following information:
    (1) The name of the biological product subject to the notification, 
including the National Drug Code for such biological product, or an 
alternative standard for identification and labeling that has been 
recognized as acceptable by the Center Director;
    (2) The name of the applicant of the biological product;
    (3) Whether the notification relates to a permanent discontinuance 
of the biological product or an interruption in manufacturing of the 
biological product;
    (4) A description of the reason for the permanent discontinuance or 
interruption in manufacturing; and
    (5) The estimated duration of the interruption in manufacturing.
    (d)(1) Public list of biological product shortages. FDA will 
maintain a publicly available list of biological products that are 
determined by FDA to be in

[[Page 38940]]

shortage. This biological product shortages list will include the 
following information:
    (i) The names and National Drug Codes for such biological products, 
or the alternative standards for identification and labeling that have 
been recognized as acceptable by the Center Director;
    (ii) The name of each applicant for such biological products;
    (iii) The reason for the shortage, as determined by FDA, selecting 
from the following categories: Requirements related to complying with 
good manufacturing practices; regulatory delay; shortage of an active 
ingredient; shortage of an inactive ingredient component; 
discontinuation of the manufacture of the biological product; delay in 
shipping of the biological product; demand increase for the biological 
product; or other reason; and
    (iv) The estimated duration of the shortage.
    (2) Confidentiality. FDA may choose not to make information 
collected to implement this paragraph available on the biological 
product shortages list or available under section 506C(c) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356c(c)) if FDA 
determines that disclosure of such information would adversely affect 
the public health (such as by increasing the possibility of hoarding or 
other disruption of the availability of the biological product to 
patients). FDA will also not provide information on the public 
shortages list or under section 506C(c) of the Federal Food, Drug, and 
Cosmetic Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), 
including trade secrets and commercial or financial information that is 
considered confidential or privileged under Sec.  20.61 of this 
chapter.
    (e) Noncompliance letters. If an applicant fails to submit a 
notification as required under paragraph (a) of this section and in 
accordance with paragraph (b) of this section, FDA will issue a letter 
to the applicant informing it of such failure.
    (1) Not later than 30 calendar days after the issuance of such a 
letter, the applicant must submit to FDA a written response setting 
forth the basis for noncompliance and providing the required 
notification under paragraph (a) of this section and including the 
information required under paragraph (c) of this section; and
    (2) Not later than 45 calendar days after the issuance of a letter 
under this paragraph, FDA will make the letter and the applicant's 
response to the letter public, unless, after review of the applicant's 
response, FDA determines that the applicant had a reasonable basis for 
not notifying FDA as required under paragraph (a) of this section.
    (f) Definitions. The following definitions of terms apply to this 
section:
    Biological product shortage or shortage means a period of time when 
the demand or projected demand for the biological product within the 
United States exceeds the supply of the biological product.
    Intended for use in the prevention or treatment of a debilitating 
disease or condition means a biological product intended for use in the 
prevention or treatment of a disease or condition associated with 
mortality or morbidity that has a substantial impact on day-to-day 
functioning.
    Life supporting or life sustaining means a biological product that 
is essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life.
    Meaningful disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of a biological 
product by a manufacturer that is more than negligible and affects the 
ability of the manufacturer to fill orders or meet expected demand for 
its product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or insignificant changes in 
manufacturing so long as the manufacturer expects to resume operations 
in a short period of time.
    Significant disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of blood or 
blood components by a manufacturer that substantially affects the 
ability of the manufacturer to fill orders or meet expected demand for 
its product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or insignificant changes in 
manufacturing so long as the manufacturer expects to resume operations 
in a short period of time.

    Dated: July 1, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-16659 Filed 7-7-15; 8:45 am]
 BILLING CODE 4164-01-P